Triazolium salts as par1 inhibitors, production thereof, and use as medicaments

ABSTRACT

The invention relates to novel compounds of formula I 
     
       
         
         
             
             
         
       
     
     where X, A − , Q1, Q2 Q3, R2, R3, R4, R5, R6, R7, R8 and R9 are each as defined below. The compounds of formula I have antithrombotic activity and inhibit especially protease-activated receptor 1 (PAR1). The invention further relates to a process for preparing the compound of formula I and to the use thereof as a medicament.

FIELD OF THE INVENTION

The invention relates to novel compounds of the formula I

where X, A⁻, Q1, Q2, Q3, R2, R3, R4, R5, R6, R7, R8 and R9 are each asdefined below. The compounds of the formula I have antithromboticactivity and inhibit especially protease-activated receptor 1 (PAR1).The invention further relates to a process for preparing the compound ofthe formula I and to the use thereof as a medicament.

BACKGROUND OF THE INVENTION

Protease-activated receptor 1 (PAR1) is a thrombin receptor whichbelongs to the class of G protein-coupled receptors (GPCR). The gene forPAR1 is located on chromosome 5q13, consists of two exons and covers aregion of about 27 kb.

PAR1 is expressed inter alia in endothelial cells, smooth muscle cells,fibroblasts, neurons and human blood platelets. On blood platelets, PAR1is an important receptor of signal transmission and is involved ininitiating the aggregation of blood platelets.

Activation of the PARs takes place by proteolytic elimination of part ofthe N terminus of the PARs, thus exposing a new N-terminal sequencewhich then activates the receptor (Pharmacol Rev 54:203-217, 2002).

The coagulation of blood is a process for controlling blood flow whichis essential for the survival of mammals. The process of coagulation andthe subsequent breakup of the clot after wound healing has taken placestarts after damage to a vessel and can be divided into four phases:

1. The phase of vascular constriction: the blood loss into the damagedarea is reduced thereby.

2. The next phase is that of platelet adhesion to the exposed collagenin the subendothelium. This primary adhesion to the matrix activates theplatelets, which then secrete various activators which lead toenhancement of the activation. These activators additionally stimulatefurther recruitment of new platelets to the site of vessel damage andpromote platelet aggregation. The platelets aggregate at the site ofvessel wall damage and form a still loose platelet plug. Activation ofplatelets further leads to presentation of phosphatidylserine andphosphatidylinositol along the cell membrane surfaces. Exposure of thesephospholipids is essential for binding and activating the multienzymecomplexes of the coagulation cascade.

3. The initially still loose platelet aggregate is crosslinked byfibrin. If the thrombus comprises only platelets and fibrin, it is awhite thrombus. If red blood corpuscles are additionally present, it isa red thrombus.

4. After wound healing, the thrombus is broken up by the action of theprotein plasmin.

Two alternative pathways lead to the formation of a fibrin clot, theintrinsic and the extrinsic pathway. These pathways are initiated bydifferent mechanisms, but in a later phase they converge to a commonpathway of the coagulation cascade. Formation of a red thrombus or aclot on the basis of a vessel wall abnormality without wound is theresult of the intrinsic pathway. Fibrin clot formation as response totissue damage or injury is the result of the extrinsic pathway. Bothpathways include a relatively large number of proteins which are knownas coagulation factors.

The intrinsic pathway requires coagulation factors VIII, IX, X, XI andXII and prekallikrein, high molecular weight kininogen, calcium ions andphospholipids from platelets. Each of these proteins leads to activationof factor X.

The intrinsic pathway is initiated when prekallikrein, high molecularweight kininogen, factor XI and XII bind to a negatively chargedsurface. This moment is referred to as the contact phase. Exposure to avessel wall collagen is the primary stimulus of the contact phase. Theresult of the contact phase processes is conversion of prekallekreininto kallekrein, which in turn activates factor XII. Factor XIIahydrolyzes further prekallekrein to kallekrein, so that the result isactivation. As the activation of factor XII increases there isactivation of factor XI which leads to release of bradykinin, avasodilator. The initial phase of vasoconstriction is terminatedthereby. Bradykinin is produced from the high molecular weightkininogen. In the presence of Ca²⁺ ions, factor XIa activates factor IX.Factor IX is a proenzyme which contains vitamin K-dependent,c-carboxyglutamate (GLA) residues. The serine protease activity becomesevident after Ca²⁺ ions have bound to these GLA residues. Several of theserine proteases in the blood coagulation cascade (factors II, VII, IXand X) contain such vitamin K-dependent GLA residues. Factor IXa cleavesfactor X and leads to activation to factor Xa. The precondition for theformation of factor IXa is the formation of a protease complex of Ca²⁺ions and factors VIIIa, IXa and X on the surface of activated platelets.One of the reactions of activated platelets is the presentation ofphosphatidylserine and phosphatidylinositol along the surfaces.Formation of the protease complex is made possible by exposure of thesephospholipids. In this process, factor VIII acts as a receptor forfactors IXa and X. Factor VIII therefore represents a cofactor in thecoagulation cascade. Activation of factor VIII with formation of factorVIIIa, the actual receptor, requires only a minimal amount of thrombin.As the concentration of thrombin increases, factor VIIIa is finallycleaved further, and inactivated, by thrombin. This dual activity ofthrombin in relation to factor VIII leads to the protease complexformation being self-limiting and thus the blood coagulation beinglocalized.

PAR1 and PAR4 play a central role in the activation of human bloodplatelets by thrombin; activation of these receptors leads tomorphological changes in blood platelets, release of ADP and aggregationof the blood platelets (Nature 413:26-27, 2001).

PAR1 inhibitors are described for example in the European patentapplications EP1391451 or EP1391452, the U.S. Pat. No. 6,063,847 and US2004/152736, and the international application WO 03/089428.

DESCRIPTION OF THE INVENTION

The compounds of the formula I show a high specific inhibition ofprotease-activated receptor 1 and are notable, compared to compoundsfrom EP1391451, for improved water solubility.

The compounds of the formula I are therefore suitable for prophylacticand therapeutic use in humans suffering from disorders associated withthromboses, embolisms, hypercoagulability or fibrotic alterations.Examples of such disorders are thrombosis, deep vein thrombosis,pulmonary embolisms, cerebral infarction, myocardial infarction, highblood pressure, inflammatory disorders, rheumatism, asthma,glomerulonephritis or osteoporosis. The compounds of the formula I canbe employed for secondary prevention and are suitable both for acute andfor long-term therapy.

The compounds of the formula I can also be employed in combination withactive ingredients which act by antithrombotic principles different fromPAR1.

1) The invention therefore relates to a compound of the formula I

and/or any stereoisomeric or tautomeric forms of the compound of theformula I and/or mixtures of these forms in any ratio, and/or aphysiologically compatible salt of the compound of the formula I, where

-   X is C—R1 or N,-   A⁻ is an anion of an organic or inorganic acid,-   Q1 is a hydrogen atom, —(C₁-C₆)-alkyl, —(C₃-C₆)-cycloalkyl,    —(C₀-C₄)-alkylene-C(O)—R11, (C₀-C₄)-alkylene-C(O)—N(R11)-R12,    —(C₀-C₄)-alkylene-C(O)—R11, —OH, —O—(C₁-C₆)-alkyl or    —O—(C₃-C₆)-cycloalkyl, where alkyl and cycloalkyl are each    unsubstituted or mono-, di- or trisubstituted independently by    —(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl or    —O—(C₃-C₆)-cycloalkyl, where some or all of the hydrogen atoms in    alkyl or cycloalkyl may be replaced by fluorine,-   Q2 and Q3 are the same or different and are each independently a    hydrogen atom, —(C₁-C₆)-alkyl or —(C₃-C₆)-cycloalkyl, where some or    all of the hydrogen atoms in alkyl or cycloalkyl may be replaced by    fluorine,-   R1, R2, R3 and R4 are the same or different and are each    independently a hydrogen atom, —(C₁-C₁₋₆)-alkyl,    —(C₃-C₆)-cycloalkyl, —O—(C₁-C₈)-alkyl, —O—(C₃-C₆)-cycloalkyl,    —(C₀-C₄)-alkylene-C(O)—N(R11)-R12, —(C₀-C₄)-alkylene-C(O)—O—R11,    —(C₀-C₄)- alkylene-N(R11)-C(O)—O—R12, —(C₀-C₄)-alkylene-C(O)—R11,    —(C₀-C₄)-alkylene-N(R11)-R12, —(C₀-C₄)-alkylene-N(R11)-C(O)—R12,    halogen, OH, —CN, —NO₂, —SO₂CH₃, —SO₂CF₃, —SF₅,    —Si[—(C₁-C₄)-alkyl]₃, —(C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl,    —O—(C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl,    —O—(C₀-C₄)-alkylene-(C₆-C₁₄)-aryl where aryl is unsubstituted or    mono-, di- or trisubstituted independently by —O—(C₁-C₆)-alkyl,    —(C₁-C₄)-alkyl, OH, —(C₃-C₆)-cycloalkyl or —O—(C₃-C₆)-cycloalkyl,    —O—(C₁-C₄)-alkylene-(C₃-C₆)-cycloalkyl, —(C₄-C₁₅)-Het, where Het is    unsubstituted or mono-, di- or trisubstituted independently by    —(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl or    —O—(C₃-C₆)-cycloalkyl, or    —O—(C₁-C₆)-alkylene-O—(C₁-C₆)-alkylene-β-(C₁-C₆)-alkyl,    -   where alkyl, alkylene and cycloalkyl are each unsubstituted or        mono-, di- or trisubstituted independently by —(C₁-C₄)-alkyl,        —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl, —(C₆-C₁₄)-aryl where        aryl is unsubstituted or mono-, di-, tri-, tetra- or        pentasubstituted independently by halogen, —(C₁-C₄)-alkyl,        —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl or        —O—(C₃-C₆)-cycloalkyl, —(C₄-C₁₅)-Het where Het is unsubstituted        or mono-, di-, tri-, tetra- or pentasubstituted independently by        halogen, —(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH,        —O—(C₁-C₆)-alkyl or —O—(C₃-C₆)-cycloalkyl,        —O—(C₃-C₆)-cycloalkyl,    -   where some or all of the hydrogen atoms in alkyl, alkylene or        cycloalkyl may be replaced by fluorine, or-   R1 and R2, R2 and R3 or R3 and R4, together with the ring atoms to    which they are each bonded, form a 5- to 8-membered ring, where the    ring consists only of carbon atoms or 1, 2 or 3 of these atoms are    replaced by nitrogen, oxygen or sulfur atoms, where the ring is    unsubstituted or mono- or disubstituted independently by    —(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl or    —O—(C₃-C₆)-cycloalkyl, where some or all of the hydrogen atoms in    the 5- to 8-membered ring formed, and in alkyl or cycloalkyl, may be    replaced by fluorine,-   R11 and R12 (should also apply to Q1!) are each independently a    hydrogen atom, —(C₁-C₆)-alkyl, —(C₃-C₆)-cycloalkyl,    —(C₀-C₄)-alkylene-(C₆-C₁₄)-aryl, —(C₀-C₄)-alkylene-(C₄-C₁₅)-Het,    —SO₂CH₃ or —SO₂CF₃,    -   where some or all of the hydrogen atoms in alkyl, alkylene or        cycloalkyl may be replaced by fluorine, or-   R11 and R12 in the “N(R11)-R12” and “N(R11)-C(O)—R12” fragments    represent a 5- to 8-membered ring which is formed together with the    nitrogen atom “N” or the “N—C(O)” group to form cyclic amines,    imides or lactams which contain up to 2 further heteroatoms from the    group of N, O and S, where the ring is unsubstituted or mono- or    disubstituted independently by —(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl,    OH, —O—(C₁-C₆)-alkyl or —O—(C₃-C₆)-cycloalkyl, where some or all of    the hydrogen atoms in the 5- to 8-membered ring formed, and in alkyl    or cycloalkyl, may be replaced by fluorine,-   R5, R6, R7, R8 and R9 are the same or different and are each    independently a hydrogen atom, —(C₁-C₆)-alkyl, —(C₃-C₆)-cycloalkyl,    OH, —CN, —NO₂, —O—(C₁-C₈)-alkyl, —O—(C₃-C₆)-cycloalkyl,    —(C₀-C₄)-alkylene-(CO)—N(R21)-R22, —SO₂CH₃, —SO₂CF₃,    —(C₀-C₄)-alkylene-C(O)—O—R21, halogen, —SF₅,    —(C₀-C₄)-alkylene-C(O)—R21, —(C₀-C₄)-alkylene-N(R21)-R22,    —(C₀-C₄)-alkylene-N(R21)-C(O)—R22,    —(C₁-C₆)-alkylene-β-(C₁-C₆)-alkyl,    —(C₀-C₆)-alkylene-O—(C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl,    —Si[—(C₁-C₄)-alkyl]₃,    —(C₀-C₆)-alkylene-O—(C₁-C₄)-alkylene-(C₃-C₆)-cycloalkyl,    —(C₀-C₆)-alkylene-O—(C₀-C₆)-alkylene-(C₆-C₁₄)-aryl or —(C₄-C₁₅)-Het,    -   where alkyl, alkylene and cycloalkyl are each unsubstituted or        mono-, di- or trisubstituted independently by —(C₁-C₄)-alkyl,        —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl, —(C₆-C₁₄)-aryl where        aryl is unsubstituted or mono-, di-, tri-, tetra- or        pentasubstituted independently by halogen,    -   —(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl or    -   —O—(C₃-C₆)-cycloalkyl,    -   —(C₄-C₁₅)-Het where Het is unsubstituted or mono-, di-, tri-,        tetra- or pentasubstituted independently by halogen,        —(C₁-C₄)-alkyl,    -   —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl or        —O—(C₃-C₆)-cycloalkyl, or —O—(C₃-C₆)-cycloalkyl,    -   where some or all of the hydrogen atoms in alkyl, alkylene or        cycloalkyl may be replaced by fluorine, or-   R5 and R6, R6 and R7, R7 and R8 or R8 and R9, together with the ring    atoms to which they are each bonded, form a 5- to 8-membered ring,    where the ring consists only of carbon atoms or 1, 2 or 3 of these    atoms are replaced by nitrogen, oxygen or sulfur atoms, where the    ring is unsubstituted or mono- or disubstituted independently by    —(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl or    —O—(C₃-C₆)-cycloalkyl, where some or all of the hydrogen atoms in    the 5- to 8-membered ring formed, and in alkyl or cycloalkyl, may be    replaced by fluorine,-   R21 and R22 are each independently a hydrogen atom, —(C₁-C₆)-alkyl,    —(C₃-C₆)-cycloalkyl, —(C₀-C₄)-alkylene-(C₆-C₁₄)-aryl,    —(C₀-C₄)-alkylene-(C₄-C₁₅)-Het, —SO₂CH₃ or —SO₂CF₃, where some or    all of the hydrogen atoms in alkyl, alkylene or cycloalkyl may be    replaced by fluorine, or-   R21 and R22 in the “N(R21)-R22” and “N(R21)-C(O)—R22” fragments    represent a 5- to 8-membered ring which is formed together with the    nitrogen atom “N” or the “N—C(O)” group to form cyclic amines,    imides or lactams which contain up to 2 further heteroatoms from the    group of N, O and S, where the ring is unsubstituted or mono- or    disubstituted independently by —(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl,    OH, —O—(C₁-C₆)-alkyl or —O—(C₃-C₆)-cycloalkyl, where some or all of    the hydrogen atoms in the 5- to 8-membered ring formed, and in alkyl    or cycloalkyl, may be replaced by fluorine.    2) Preference is given to a compound of the formula I wherein-   X is C—R1 or N,-   A⁻ is an anion of an organic or inorganic acid,-   Q1 is a hydrogen atom, —(C₁-C₆)-alkyl, —(C₃-C₆)-cycloalkyl,    —(C₀-C₄)-alkylene-C(O)—O—R11, —(C₀-C₄)-alkylene-C(O)—N(R11)-R12,    —(C₀-C₄)-alkylene-C(O)—R11, —OH, —O—(C₁-C₆)-alkyl or    -   —O—(C₃-C₆)-cycloalkyl, where alkyl and cycloalkyl are each        unsubstituted or mono-, di- or trisubstituted independently by        —(C₁-C₄)-alkyl,    -   —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl or        —O—(C₃-C₆)-cycloalkyl, where some or all of the hydrogen atoms        in alkyl or cycloalkyl may be replaced by fluorine,-   Q2 and Q3 are the same or different and are each independently a    hydrogen atom, —(C₁-C₆)-alkyl or —(C₃-C₆)-cycloalkyl, where some or    all of the hydrogen atoms in alkyl or cycloalkyl may be replaced by    fluorine,-   R1, R2, R3 and R4 are the same or different and are each    independently a hydrogen atom, —(C₁-C₆)-alkyl, —(C₃-C₆)-cycloalkyl,    —O—(C₁-C₈)-alkyl, —O—(C₃-C₆)-cycloalkyl,    —(C₀-C₄)-alkylene-C(O)—N(R11)-R12,    —(C₀-C₄)-alkylene-N(R11)-C(O)—O—R12, —(C₀-C₄)-alkylene-C(O)—O—R11,    —(C₀-C₄)-alkylene-C(O)—R11, —(C₀-C₄)-alkylene-N(R11)-R12,    —(C₀-C₄)-alkylene-N(R11)-C(O)—R12, halogen, OH, —CN, —NO₂, —SO₂CH₃,    —SO₂CF₃, —SF₅, —Si[—(C₁-C₄)-alkyl]₃,    —(C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl,    —O—(C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl,    —O—(C₀-C₄)-alkylene-(C₆-C₁₄)-aryl where aryl is unsubstituted or    mono-, di- or trisubstituted independently by —O—(C₁-C₆)-alkyl,    —(C₁-C₄)-alkyl, OH, —(C₃-C₆)-cycloalkyl or —O—(C₃-C₆)-cycloalkyl,    —O—(C₁-C₄)-alkylene-(C₃-C₆)-cycloalkyl, —(C₄-C₁₅)-Het,    -   where Het is unsubstituted or mono-, di- or trisubstituted        independently by —(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH,        —O—(C₁-C₆)-alkyl or —O—(C₃-C₆)-cycloalkyl, or        —O—(C₁-C₆)-alkylene-O—(C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl,    -   where alkyl, alkylene and cycloalkyl are each unsubstituted or        mono-, di- or trisubstituted independently by —(C₁-C₄)-alkyl,        —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl, —(C₆-C₁₄)-aryl where        aryl is unsubstituted or mono-, di-, tri-, tetra- or        pentasubstituted independently by halogen, —(C₁-C₄)-alkyl,        —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl or        —O—(C₃-C₆)-cycloalkyl, —(C₄-C₁₅)-Het where Het is unsubstituted        or mono-, di-, tri-, tetra- or pentasubstituted independently by        halogen, —(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH,        —O—(C₁-C₆)-alkyl or —O—(C₃-C₆)-cycloalkyl, or        —O—(C₃-C₆)-cycloalkyl,    -   where some or all of the hydrogen atoms in alkyl, alkylene or        cycloalkyl may be replaced by fluorine,        with the proviso that at least one R1, R2, R3 or R4 is not a        hydrogen atom or-   R1 and R2, R2 and R3 or R3 and R4, together with the ring atoms to    which they are each bonded, form a 5- to 8-membered ring, where the    ring consists only of carbon atoms or 1, 2 or 3 of these atoms are    replaced by nitrogen, oxygen or sulfur atoms, where the ring is    unsubstituted or mono- or disubstituted independently by    —(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl or    —O—(C₃-C₆)-cycloalkyl, where some or all of the hydrogen atoms in    the 5- to 8-membered ring formed, and in alkyl or cycloalkyl, may be    replaced by fluorine,-   R11 and R12 are each independently a hydrogen atom, —(C₁-C₆)-alkyl,    —(C₃-C₆)-cycloalkyl, —(C₀-C₄)-alkylene-(C₆-C₁₄)-aryl,    —(C₀-C₄)-alkylene-(C₄-C₁₅)-Het, —SO₂CH₃ or —SO₂CF₃,    -   where some or all of the hydrogen atoms in alkyl, alkylene or        cycloalkyl may be replaced by fluorine, or-   R11 and R12 in the “N(R11)-R12” and “N(R11)-C(O)—R12” fragments    represent a 5- to 8-membered ring which is formed together with the    nitrogen atom “N” or the “N—(CO)” group to form cyclic amines,    imides or lactams which contain up to 2 further heteroatoms from the    group of N, O and S, where the ring is unsubstituted or mono- or    disubstituted independently by —(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl,    OH, —O—(C₁-C₆)-alkyl or —O—(C₃-C₆)-cycloalkyl, where some or all of    the hydrogen atoms in the 5- to 8-membered ring formed, and in alkyl    or cycloalkyl, may be replaced by fluorine,-   R4, R5, R6, R7, R8 and R9 are the same or different and are each    independently a hydrogen atom, —(C₁-C₆)-alkyl, —(C₃-C₆)-cycloalkyl,    OH, —CN, —NO₂, —O—(C₁-C₈)-alkyl, —O—(C₃-C₆)-cycloalkyl,    —(C₀-C₄)-alkylene-(C(O)—N(R21)-R22, —SO₂CH₃, —SO₂CF₃,    —(C₀-C₄)-alkylene-C(O)—O—R21, halogen, —SF₅,    —(C₀-C₄)-alkylene-C(O)—R21, —(C₀-C₄)-alkylene-N(R21)-R22,    —(C₀-C₄)-alkylene-N(R21)-C(O)—R22,    —(C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl,    —(C₀-C₆)-alkylene-O—(C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl,    —Si[—(C₁-C₄)-alkyl]₃,    —(C₀-C₆)-alkylene-O—(C₁-C₄)-alkylene-(C₃-C₆)-cycloalkyl,    —(C₀-C₆)-alkylene-O—(C₀-C₆)-alkylene-(C₆-C₁₄)-aryl or —(C₄-C₁₅)-Het,    -   where alkyl, alkylene and cycloalkyl are each unsubstituted or        mono-, di- or trisubstituted independently by —(C₁-C₄)-alkyl,        —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl, —(C₆-C₁₄)-aryl where        aryl is unsubstituted or mono-, di-, tri-, tetra- or        pentasubstituted independently by halogen,    -   —(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl or    -   —O—(C₃-C₆)-cycloalkyl,    -   —(C₄-C₁₅)-Het where Het is unsubstituted or mono-, di-, tri-,        tetra- or pentasubstituted independently by halogen,        —(C₁-C₄)-alkyl,    -   —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl or        —O—(C₃-C₆)-cycloalkyl, or —O—(C₃-C₆)-cycloalkyl,    -   where some or all of the hydrogen atoms in alkyl, alkylene or        cycloalkyl may be replaced by fluorine,        with the proviso that at least one R5, R6, R7, R8 or R9 is not a        hydrogen atom, or-   R5 and R6, R6 and R7, R7 and R8 or R8 and R9, together with the ring    atoms to which they are each bonded, form a 5- to 8-membered ring,    where the ring consists only of carbon atoms or 1, 2 or 3 of these    atoms are replaced by nitrogen, oxygen or sulfur atoms, where the    ring is unsubstituted or mono- or disubstituted independently by    —(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl or    -   —O—(C₃-C₆)-cycloalkyl, where some or all of the hydrogen atoms        in the 5- to 8-membered ring formed, and in alkyl or cycloalkyl,        may be replaced by fluorine,-   R21 and R22 are each independently a hydrogen atom, —(C₁-C₆)-alkyl,    —(C₃-C₆)-cycloalkyl, —(C₀-C₄)-alkylene-(C₆-C₁₄)-aryl,    —(C₀-C₄)-alkylene-(C₄-C₁₅)-Het, —SO₂CH₃ or —SO₂CF₃,    -   where some or all of the hydrogen atoms in alkyl, alkylene or        cycloalkyl may be replaced by fluorine, or-   R21 and R22 in the “N(R21)-R22” and “N(R21)-C(O)—R22” fragments    represent a 5- to 8-membered ring which is formed together with the    nitrogen atom “N” or the “N—C(O)” group to form cyclic amines,    imides or lactams which contain up to 2 further heteroatoms from the    group of N, O and S, where the ring is unsubstituted or mono- or    disubstituted independently by —(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl,    OH, —O—(C₁-C₆)-alkyl or —O—(C₃-C₆)-cycloalkyl, where some or all of    the hydrogen atoms in the 5- to 8-membered ring formed, and in alkyl    or cycloalkyl, may be replaced by fluorine.    3) Particular preference is given to a compound of the formula I,    wherein-   X is C—R1 or N,-   A⁻ is an anion of an organic or inorganic acid,-   Q1 is a hydrogen atom, —(C₁-C₆)-alkyl, —(C₃-C₆)-cycloalkyl,    —(C₀-C₄)-alkylene-C(O)—O—R11, —(C₀-C₄)-alkylene-C(O)—N(R11)-R12,    —(C₀-C₄)-alkylene-C(O)—R11, —OH, —O—(C₁-C₆)-alkyl or    -   —O—(C₃-C₆)-cycloalkyl, where alkyl and cycloalkyl are each        unsubstituted or mono-, di- or trisubstituted independently by        —(C₁-C₄)-alkyl,    -   —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl or        —O—(C₃-C₆)-cycloalkyl, where some or all of the hydrogen atoms        in alkyl or cycloalkyl may be replaced by fluorine,-   Q2 and Q3 are the same or different and are each independently a    hydrogen atom, —(C₁-C₆)-alkyl or —(C₃-C₆)-cycloalkyl, where some or    all of the hydrogen atoms in alkyl or cycloalkyl may be replaced by    fluorine,-   R1, R2, R3 and R4 are the same or different and are each    independently a hydrogen atom, —(C₁-C₆)-alkyl, —(C₃-C₆)-cycloalkyl,    —O—(C₁-C₈)-alkyl, —O—(C₃-C₆)-cycloalkyl,    —(C₀-C₄)-alkylene-C(O)—N(R11)-R12, —(C₀-C₄)-alkylene-C(O)—O—R11,    —(C₀-C₄)-alkylene-N(R11)-C(O)—O—R12, —(C₀-C₄)-alkylene-C(O)—R11,    —(C₀-C₄)-alkylene-N(R11)-R12, —(C₀-C₄)-alkylene-N(R11)-C(O)—R12,    halogen, OH, —CN, —NO₂, —SO₂CH₃, —Si[—(C₁-C₄)-alkyl]₃,    —(C₁-C₆)-alkylene-β-(C₁-C₆)-alkyl,    —O—(C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl,    —O—(C₀-C₄)-alkylene-(C₆-C₁₄)-aryl,    —O—(C₁-C₄)-alkylene-(C₃-C₆)-cycloalkyl, —(C₄-C₁₅)-Het or    —O—(C₁-C₆)-alkylene-O—(C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl,    -   where alkyl, alkylene and cycloalkyl are each unsubstituted or        mono-, di- or trisubstituted independently by —(C₁-C₄)-alkyl,        —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl or        —O—(C₃-C₆)-cycloalkyl,    -   where some or all of the hydrogen atoms in alkyl, alkylene or        cycloalkyl may be replaced by fluorine,        with the proviso that at least one R1, R2, R3 or R4 is not a        hydrogen atom or-   R1 and R2, R2 and R3 or R3 and R4, together with the ring atoms to    which they are each bonded, form a ring selected from the group of    2,3,5,6,7,8-hexahydro-1,2,3a,4,5,8-hexaaza-cyclopenta[b]naphthalene;    2,6,7,8-tetrahydro-3H-5-oxa-1,2,3a,4,8-pentaaza-cyclopenta[b]naphthalene;    2,3,6,7-tetrahydro-5,8-dioxa-1,2,3a,4-tetraaza-cyclopenta[b]naphthalene;    2,3,6,7-tetrahydro-5H-8-oxa-1,2,3a,4,5-pentaaza-cyclopenta[b]naphthalene;    2,6,7,8-tetrahydro-3H-5-thia-1,2,3a,4,8-pentaaza-cyclopenta[b]naphthalene;    2,3,6,7,8,9-hexahydro-1,2,3a,4,6,9-hexaaza-cyclopenta[a]-naphthalene;    2,3-dihydro-5,7-dioxa-1,2,3a,4-tetraaza-s-indacene;    2,6,7,8-tetrahydro-3H-cyclopenta[e][1,2,4]triazolo[4,3-b]pyridazine;    2,7,8,9-tetrahydro-3H-cyclopenta[d][1,2,4]triazolo[4,3-b]pyridazine    and    2,3,6a,9a-tetrahydro-[1,3]dioxolo[4,5-d][1,2,4]triazolo[4,3-b]pyridazine,    where the ring is unsubstituted or mono- or disubstituted    independently by —(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH, —O    —(C₁-C₆)-alkyl or —O—(C₃-C₆)-cycloalkyl, where some or all of the    hydrogen atoms in the 5- to 8-membered ring formed, and in alkyl or    cycloalkyl, may be replaced by fluorine,-   R11 and R12 are each independently a hydrogen atom, —(C₁-C₆)-alkyl,    —(C₃-C₆)-cycloalkyl, —(C₀-C₄)-alkylene-(C₆-C₁₄)-aryl,    —(C₀-C₄)-alkylene-(C₄-C₁₅)-Het, —SO₂CH₃ or —SO₂CF₃,    -   where some or all of the hydrogen atoms in alkyl, alkylene or        cycloalkyl may be replaced by fluorine, or-   R11 and R12 in the “N(R11)-R12” and “N(R11)-C(O)—R12” fragments    represent a 5- to 8-membered ring selected from the group of    azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepinyl,    morpholinyl, thiomorpholinyl, pyrrolidine-2,5-dionyl,    piperidine-2,6-dionyl, piperazine-2,6-dionyl, morpholine-3,5-dionyl,    pyrrolidin-2-onyl, piperidin-2-onyl, piperazin-2-onyl and    morpholin-3-onyl, where the ring is unsubstituted or mono- or    disubstituted independently by —(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl,    OH, —O —(C₁-C₆)-alkyl or —O—(C₃-C₆)-cycloalkyl where some or all of    the hydrogen atoms in the 5- to 8-membered ring formed, and in alkyl    or cycloalkyl, may be replaced by fluorine,-   R4, R5, R6, R7, R8 and R9 are the same or different and are each    independently a hydrogen atom, —(C₁-C₆)-alkyl, —(C₃-C₆)-cycloalkyl,    OH, —CN, —NO₂, —O—(C₁-C₈)-alkyl, —O—(C₃-C₆)-cycloalkyl, —SO₂CH₃,    —SO₂CF₃, —(C₀-C₄)-alkylene-(CO)—N(R21)-R22,    —(C₀-C₄)-alkylene-C(O)—O—R21, halogen, —SF₅,    —(C₀-C₄)-alkylene-C(O)—R21, —(C₀-C₄)-alkylene-N(R21)-R22,    —(C₀-C₄)-alkylene-N(R21)-C(O)—R22,    —(C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl,    —(C₀-C₆)-alkylene-O—(C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl,    —Si[—(C₁-C₄)-alkyl]₃,    —(C₀-C₆)-alkylene-O—(C₁-C₄)-alkylene-(C₃-C₆)-cycloalkyl,    —(C₀-C₆)-alkylene-O—(C₀-C₆)-alkylene-(C₆-C₁₄)-aryl or —(C₄-C₁₅)-Het,    -   where alkyl, alkylene and cycloalkyl are each unsubstituted or        mono-, di- or trisubstituted independently by —(C₁-C₄)-alkyl,        —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl, —(C₆-C₁₄)-aryl where        aryl is unsubstituted or mono-, di-, tri-, tetra- or        pentasubstituted independently by halogen,    -   —(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl or        —O—(C₃-C₆)-cycloalkyl,    -   —(C₄-C₁₅)-Het where Het is unsubstituted or mono-, di-, tri-,        tetra- or pentasubstituted independently by halogen,        —(C₁-C₄)-alkyl,    -   —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl or        —O—(C₃-C₆)-cycloalkyl, or —O—(C₃-C₆)-cycloalkyl,    -   where some or all of the hydrogen atoms in alkyl, alkylene or        cycloalkyl may be replaced by fluorine,        with the proviso that at least one R5, R6, R7, R8 or R9 is not a        hydrogen atom, or-   R5 and R6, R6 and R7, R7 and R8 or R8 and R9, together with the ring    atoms to which they are each bonded, form a 5- to 8-membered ring    selected from the group of 2,3-dihydrobenzo[1,4]dioxin;    3,4-dihydro-2H-benzo[1,4]oxazine; 1,2,3,4-tetrahydro-quinoxaline;    benzo[1,3]dioxole; 3,4-dihydro-2H-benzo[1,4]thiazine and    2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine,    -   where the ring is unsubstituted or mono- or disubstituted        independently by —(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH,        —O—(C₁-C₆)-alkyl or —O—(C₃-C₆)-cycloalkyl, where some or all of        the hydrogen atoms in the 5- to 8-membered ring formed, and in        alkyl or cycloalkyl, may be replaced by fluorine,-   R21 and R22 are each independently a hydrogen atom, —(C₁-C₆)-alkyl,    —(C₃-C₆)-cycloalkyl, —(C₀-C₄)-alkylene-(C₆-C₁₄)-aryl,    —(C₀-C₄)-alkylene-(C₄-C₁₅)-Het, —SO₂CH₃ or —SO₂CF₃,    -   where some or all of the hydrogen atoms in alkyl, alkylene or        cycloalkyl may be replaced by fluorine, or-   R21 and R22 in the “N(R21)-R22” and “N(R21)-C(O)—R22” fragments    represent a 5- to 8-membered ring selected from the group of    azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepinyl,    morpholinyl, thiomorpholinyl, pyrrolidine-2,5-dionyl,    piperidine-2,6-dionyl, piperazine-2,6-dionyl, morpholine-3,5-dionyl,    pyrrolidin-2-onyl, piperidin-2-onyl, piperazin-2-onyl and    morpholin-3-onyl, where the ring is unsubstituted or mono- or    disubstituted independently by —(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl,    OH, —O—(C₁-C₆)-alkyl or —O—(C₃-C₆)-cycloalkyl, where some or all of    the hydrogen atoms in the 5- to 8-membered ring formed, and in alkyl    or cycloalkyl, may be replaced by fluorine.    4) The invention further relates to a compound of the formula I,    wherein-   X is C—R1 or N,-   A⁻ is an anion of an organic or inorganic acid,-   Q1 is a hydrogen atom, —(C₁-C₆)-alkyl, —(C₃-C₆)-cycloalkyl,    —(C₀-C₄)-alkylene-C(O)—O—R11, —(C₀-C₄)-alkylene-C(O)—N(R11)-R12,    —(C₀-C₄)-alkylene-C(O)—R11, —OH, —O—(C₁-C₆)-alkyl or    -   —O—(C₃-C₆)-cycloalkyl, where alkyl and cycloalkyl are each        unsubstituted or mono-, di- or trisubstituted independently by        —(C₁-C₄)-alkyl,    -   —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl or        —O—(C₃-C₆)-cycloalkyl, where some or all of the hydrogen atoms        in alkyl or cycloalkyl may be replaced by fluorine,-   Q2 and Q3 are the same or different and are each independently a    hydrogen atom, —(C₁-C₆)-alkyl or —(C₃-C₆)-cycloalkyl, where some or    all of the hydrogen atoms in alkyl or cycloalkyl may be replaced by    fluorine,-   R1, R2, R3 and R4 are the same or different and are each    independently a hydrogen atom, —(C₁-C₄)-alkyl, —O—(C₁-C₈)-alkyl,    —O—(C₃-C₆)-cycloalkyl, —(C₀-C₄)-alkylene-C(O)—N(R11)-R12,    —(C₀-C₄)-alkylene-C(O)—O—R11, —CF₃,    —(C₀-C₄)-alkylene-N(R11)-C(O)—O—R12, —(C₀-C₄)-alkylene-N(R11)-R12,    chlorine, —O—(C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl,    —O—(C₀-C₄)-alkylene-(C₆-C₁₄)-aryl or —(C₄-C₁₅)-Het where Het is    selected from the group of acridinyl, azepinyl, azetidinyl,    benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl,    benzoxazolyl, benzothiazolyl, benzotriazolyl, benzisoxazolyl,    benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl,    quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,    quinuclidinyl, chromanyl, chromenyl, cinnolinyl,    deca-hydroquinolinyl, dibenzofuranyl, dibenzothiophenyl,    dihydrofuran[2,3-b]tetrahydrofuranyl, dihydrofuranyl, dioxolyl,    dioxanyl, 2H, 6H-1,5,2-dithiazinyl, furanyl, furazanyl,    imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl,    indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isoquinolinyl,    isochromanyl, isoindazolyl, isoindolinyl, isoindolyl,    isothiazolidinyl, 2-isothiazolinyl, isothiazolyl, isoxazolyl,    isoxazolidinyl, 2-isoxazolinyl, morpholinyl, naphthyridinyl,    octahydroisoquinolinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,    1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl,    oxothiolanyl, phenanthridinyl, phenanthrolinyl, phenazinyl,    phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,    piperazinyl, piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl,    pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl,    pyridoimidazolyl, pyridothiazolyl, pyridothiophenyl, pyridyl,    pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl,    tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,    tetrahydropyridinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,    1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,    thianthrenyl, thiazolidinyl, thiazolinyl, thiazolyl, thienyl,    thienoimidazolyl, thienooxazolyl, thienopyrrol, thienopyridin,    thienothiazolyl, thienothiophenyl, thiomorpholinyl, triazinyl,    1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl    and xanthenyl,    -   where alkylene is unsubstituted or monosubstituted by        —(C₁-C₄)-alkyl or —(C₃-C₆)-cycloalkyl, or some or all of the        hydrogen atoms in alkylene are replaced by fluorine,-   R11 and R12 are each independently a hydrogen atom or    —(C₁-C₆)-alkyl,-   R5, R6, R7, R8 and R9 are the same or different and are each    independently a hydrogen atom, —(C₁-C₆)-alkyl, OH, —O—(C₁-C₈)-alkyl,    chlorine, bromine, —SF₅, —(C₀-C₄)-alkylene-N(R21)-R22,    —(C₀-C₄)-alkylene-N(R21)-C(O)—R22,    (C₀-C₆)-alkylene-O—(C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl, —(C₄-C₁₅)-Het,    —(C₀-C₆)-alkylene-O—(C₁-C₄)-alkylene-(C₃-C₆)-cycloalkyl, —CF₃— or    —(C₀-C₆)-alkylene-O—(C₀-C₆)-alkylene-(C₆-C₁₄)-aryl,    -   where alkylene is unsubstituted or monosubstituted by    -   —O—(C₁-C₆)-alkyl,        with the proviso that at least one R5, R6, R7, R8 or R9 is not a        hydrogen atom,-   R5 and R6, R6 and R7 or R7, or R8 and R9, together with the ring    atoms to which they are each bonded, form a morpholine ring, where    the ring is unsubstituted or monosubstituted by —(C₁-C₄)-alkyl,-   R21 and R22 are each independently a hydrogen atom or    —(C₁-C₆)-alkyl.    5) Exceptionally preferred are compounds of the formula I including    the following compounds:-   1-{2-[3-acetylamino-5-(pentafluorosulfanyl)phenyl]-2-oxoethyl}-3-amino-6-ethoxy-[1,2,4]-triazolo[4,3-b]pyridazin-1-ium    as trifluoroacetic acid salt,-   3-amino-1-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxoethyl]-6-trifluoromethyl-[1,2,4]triazolo[4,3-a]pyridin-1-ium,-   3-amino-1-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxoethyl]-[1,2,4]triazolo[4,3-a]pyridin-1-ium,-   3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-trifluoromethyl-[1,2,4]triazolo[4,3-a]pyridin-1-ium,-   3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-5-methyl-7-trifluoromethyl-[1,2,4]triazolo[4,3-a]pyridin-1-ium,-   3-amino-5-chloro-1-{2-[3-methylamino-5-(pentafluorosulfanyl)phenyl]-2-oxoethyl}-[1,2,4]triazolo[4,3-a]pyridin-1-ium,-   3-amino-7-ethoxy-6-ethoxycarbonyl-1-{2-[3-methylamino-5-(pentafluorosulfanyl)phenyl]-2-oxoethyl}-[1,2,4]triazolo[4,3-a]pyridin-1-ium,-   3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-7-ethoxy-6-ethoxycarbonyl-[1,2,4]triazolo[4,3-a]pyridin-1-ium,-   3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-7-ethoxy-6-methylcarbamoyl-[1,2,4]triazolo[4,3-a]pyridin-1-ium,-   3-amino-6-chloro-1-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxoethyl]-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxo-ethyl]-6-ethoxy-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-isopropoxy-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-methoxy-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-6-ethoxy-1-[2-(4-methoxy-3-morpholin-4-yl-5-trifluoromethylphenyl)-2-oxoethyl]-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   1-{2-[3-acetylamino-5-(pentafluorosulfanyl)phenyl]-2-oxoethyl}-3-amino-6-ethoxy-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-cyclopentyloxy-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-cyclobutoxy-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-phenoxy-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-6-benzyloxy-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-cyclohexyloxy-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-yl-phenyl)-2-oxoethyl]-6-(2,2,2-trifluoroethoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-cyclopropyl-methoxy-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-ethoxy-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-6-(1-ethyl-propoxy)-1-{2-[3-methylamino-5-(pentafluorosulfanyl)phenyl]-2-oxoethyl}-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-6-(1-ethylpropoxy)-1-{2-[3-methoxy-5-(pentafluorosulfanyl)phenyl]-2-oxoethyl}-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(3-tert-butyl-5-ethoxymethylphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(3-tert-butyl-5-cyclopropylmethoxymethylphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(3-tert-butyl-4,5-diethoxyphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(3-tert-butyl-4,5-biscyclopropylmethoxyphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(3-tert-butyl-5-propoxymethylphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(3-tert-butyl-5-ethoxyphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo-[4,3-b]pyridazin-1-ium,-   3-amino-6-(1-ethylpropoxy)-1-[2-(3-methoxy-5-trifluoromethylphenyl)-2-oxoethyl]-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(3-tert-butyl-5-methoxyphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(3-tert-butyl-5-cyclopropylmethoxyphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(3-tert-butyl-5-cyclobutylmethoxyphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(3-benzyloxymethyl-5-tert-butylphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(3-cyclohexylmethoxy-4,5-dimethoxyphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-6-butoxy-1-[2-(3-tert-butyl-5-methoxymethylphenyl)-2-oxoethyl]-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(3-chloro-5-methoxyphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(8-tert-butyl-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-diethylamino-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-piperidin-1-yl-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-ethoxy-[1,2,4]triazolo[4,3-a]pyridin-1-ium,-   3-amino-1-[2-(3-cyclohexylmethoxy-5-ethoxyphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(3-bromo-5-methoxyphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo-[4,3-b]pyridazin-1-ium,-   3-amino-6-(1-ethylpropoxy)-1-[2-(3-isopropyl-5-methoxyphenyl)-2-oxoethyl]-[1,2,4]triazolo-[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(3-cyclohexylmethoxy-5-methoxyphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-{2-[3-(3,3-dimethylbutoxy)-5-ethoxyphenyl]-2-oxoethyl}-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(8-tert-butyl-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-2-oxoethyl]-6-ethoxy-[1,2,4]triazolo[4,3-a]pyridin-1-ium,-   3-amino-6-diethylamino-1-{2-[3-methoxy-5-(pentafluorosulfanyl)phenyl]-2-oxoethyl}-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-morpholin-4-yl-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(5-bromo-2,3-dimethoxyphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(3-chloro-4,5-dimethoxyphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]-triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-{2-[3-tert-butyl-5-(2-methoxyethoxy)phenyl]-2-oxoethyl}-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(3-tert-butyl-5-methoxyphenyl)-2-oxoethyl]-6-(2-methoxyethoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(3-tert-butyl-5-methoxymethylphenyl)-2-oxoethyl]-6-(2-methoxy-ethoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-yl-phenyl)-2-oxoethyl]-6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-6-(1-ethylpropoxy)-1-{2-[3-morpholin-4-yl-5-(pentafluorosulfanyl)phenyl]-2-oxoethyl}-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-6-ethyl-1-{2-[3-methoxy-5-(pentafluorosulfanyl)phenyl]-2-oxoethyl}-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-ethyl-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,-   3-amino-6-chloro-7-diethylcarbamoyl-1-{2-[3-methoxy-5-(pentafluorosulfanyl)phenyl]-2-oxoethyl}-[1,2,4]triazolo[4,3-b]pyridazin-1-ium    or-   3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-chloro-7-diethylcarbamoyl-[1,2,4]triazolo[4,3-b]pyridazin-1-ium.

The term “anion” is understood to mean anions of organic and inorganicacids, particular preference being given to chloride. Examples ofinorganic or organic acids are hydrochloric acid, hydrobromic acid,sulfuric acid, hemisulfuric acid, phosphoric acid, methanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, 4-bromobenzenesulfonicacid, cyclohexylamidosulfonic acid, trifluoromethylsulfonic acid,2-hydroxyethanesulfonic acid, acetic acid, oxalic acid, tartaric acid,succinic acid, glycerolphosphoric acid, lactic acid, malic acid, adipicacid, citric acid, fumaric acid, maleic acid, gluconic acid, glucuronicacid, palmitic acid or trifluoroacetic acid.

The expression “(C₁-C₄)-alkyl” or “(C₁-C₆)-alkyl” is understood to meanhydrocarbon radicals whose carbon chain is straight-chain or branchedand contains from 1 to 4 carbon atoms or from 1 to 6 carbon atoms, forexample methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl,2,3-dimethylbutyl or neohexyl.

The expression “—(C₀-C₄)-alkylene” or “—(C₁-C₆)-alkylene” is understoodto mean hydrocarbon radicals whose carbon chain is straight-chain orbranched and contains 1 to 4 or 1-6 carbon atoms, for example methylene,ethylene, 1-methylmethylene, propylene, 1-methylethylene, butylene,1-propylmethylene, 1-ethyl-1-methylmethylene, 1,2-dimethylethylene,1,1-dimethylmethylene, 1-ethylethylene, 1-methylpropylene,2-methylpropylene, pentylene, 1-methylbutylene, hexylene,1-methylpentylene. “—C₀-alkylene” is a covalent bond.

The expression “—O—(C₁-C₆)-alkyl” or “—O—(C₁-C₈)-alkyl” is understood tomean alkoxy radicals whose carbon chain is straight-chain or branchedand contains from 1 to 6 or from 1 to 8 carbon atoms, for examplemethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy,1-pentoxy, 2-pentoxy, 3-pentoxy, 1-hexoxy, 2-hexoxy, 3-hexoxy,1-heptoxy, 2-heptoxy, 3-heptoxy, 4-heptoxy, 2,4-dimethylpentan-3-oxy,1-octoxy, 2-octoxy, 3-octoxy, 2,2,4-trimethylpentan-3-oxy,2,3,4-trimethylpentan-3-oxy or 4-octoxy.

The expression “(C₃-C₆)-cycloalkyl” is understood to mean radicals suchas compounds which derive from 3- to 6-membered monocycles such ascyclopropane, cyclobutane, cyclopentane or cyclohexane.

The expression “—O—(C₃-C₆)-cycloalkyl” is understood to mean cycloalkoxyradicals such as compounds which derive from 3- to 6-membered monocyclessuch as cyclopropoxy, cyclobutoxy, cyclopentoxy or cyclohexoxy.

The expression “—(C₆-C₁₄)-aryl” is understood to mean aromatic carbonradicals having from 6 to 14 carbon atoms in the ring. —(C₆-C₁₄)-Arylradicals are, for example, phenyl, naphthyl, for example 1-naphthyl,2-naphthyl, anthryl or fluorenyl. Naphthyl radicals and especiallyphenyl are preferred aryl radicals.

The expression “Het” is understood to mean ring systems having from 4 to15 carbon atoms which are present in one, two or three ring systemsjoined to one another and which, according to ring size, may containone, two, three or four identical or different heteroatoms from thegroup of oxygen, nitrogen and sulfur. Examples of these ring systems areacridinyl, azepinyl, azetidinyl, benzimidazolyl, benzofuranyl,benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl,benzotriazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl,4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl,quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, dibenzofuranyl, dibenzothiophenyl,dihydrofuran[2,3-b]-tetrahydrofuranyl, dihydrofuranyl, dioxolyl,dioxanyl, 2H,6H-1,5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl,3H-indolyl, isobenzofuranyl, isoquinolinyl, isochromanyl, isoindazolyl,isoindolinyl, isoindolyl, isothiazolidinyl, 2-isothiazolinyl,isothiazolyl, isoxazolyl, isoxazolidinyl, 2-isoxazolinyl, morpholinyl,naphthyridinyl, octahydroisoquinolinyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxothiolanyl, phenanthridinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl, pyroazolidinyl,pyrazolinyl, pyrazolyl, pyridazinyl, pryidooxazolyl, pyridoimidazolyl,pyridothiazolyl, pyridothiophenyl, pyridyl, pyrimidinyl, pyrrolidinyl,pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyridinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolidinyl,thiazolinyl, thiazolyl, thienyl, thienoimidazolyl, thienooxazolyl,thienopyrrolyl, thienopyridyl, thienothiazolyl, thienothiophenyl,thiomorpholinyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,5-triazolyl, 1,3,4-triazolyl or xanthenyl radicals.

In the case that X is C—R1 and Y is C—R2 and R1 and R2 are each ahydrogen atom, this is understood to mean bicyclic ring systems which,together with the 4H-[1,2,4]triazol-3-ylamine in formula I form, forexample, a [1,2,4]triazolo[4,3-a]pyrin-3-ylamine ring which has thefollowing structure:

In the case that X is N and Y is C—R2 and R2 is a hydrogen atom, this isunderstood to mean bicyclic ring systems which, together with the4H-[1,2,4]triazol-3-ylamine in formula I, form, for example, a[1,2,4]triazole[4,3-b]pyridazin-3-ylamine ring which has the followingstructure:

The expression “R1 and R2, R2 and R3 or R3 and R4, together with thering atoms to which they are each bonded, form a 5- to 8-membered ring,where the ring consists only of carbon atoms or 1, 2 or 3 of these atomsare replaced by nitrogen, oxygen or sulfur atoms” is understood to mean,for example, ring systems such as2,3,5,6,7,8-hexahydro-1,2,3a,4,5,8-hexaaza-cyclopenta[b]naphthalene;2,6,7,8-tetrahydro-3H-5-oxa-1,2,3a,4,8-pentaaza-cyclopenta[b]naphthalene;2,3,6,7-tetrahydro-5,8-dioxa-1,2,3a,4-tetraaza-cyclopenta[b]naphthalene;2,3,6,7-tetrahydro-5H-8-oxa-1,2,3a,4,5-pentaaza-cyclopenta[b]naphthalene;2,6,7,8-tetrahydro-3H-5-thia-1,2,3a,4,8-pentaaza-cyclopenta[b]naphthalene;2,3,6,7,8,9-hexahydro-1,2,3a,4,6,9-hexaaza-cyclopenta[a]-naphthalene;2,3-dihydro-5,7-dioxa-1,2,3a,4-tetraaza-s-indacene;2,6,7,8-tetrahydro-3H-cyclopenta[e][1,2,4]triazolo[4,3-b]pyridazine;2,7,8,9-tetrahydro-3H-cyclopenta[d][1,2,4]triazolo[4,3-b]pyridazine or2,3,6a,9a-tetrahydro-[1,3]dioxolo[4,5-d][1,2,4]-triazolo[4,3-b]pyridazine.

The expression “R5 and R6, R6 and R7, R7 and R8 or R8 and R9, togetherwith the ring atoms to which they are each bonded, form a 5- to8-membered ring, where the ring consists only of carbon atoms or 1, 2 or3 of these atoms are replaced by nitrogen, oxygen or sulfur atoms” isunderstood to mean, for example, ring systems such as2,3-dihydrobenzo[1,4]dioxin; 3,4-dihydro-2H-benzo[1,4]oxazine;1,2,3,4-tetrahydroquinoxaline; benzo[1,3]dioxole;3,4-dihydro-2H-benzo[1,4]thiazine or2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine.

The expressions “R11 and R12 in the “N(R11)-R12” and “N(R11)-C(O)—R12”fragments represent a 5- to 8-membered ring which is formed togetherwith the nitrogen atom “N” or the “N—(CO)” group to form cyclic amines,imides or lactams which contain up to 2 further heteroatoms from thegroup of N, O and S″ or “R11 and R12 in the “N(R21)-R22” and“N(R21)-C(O)—R22” fragments is a 5- to 8-membered ring which is formedtogether with the nitrogen atom “N” or the “N—(CO)” group to form cyclicamines, imides or lactams which contain up to 2 further heteroatoms fromthe group of N, O and S″ is understood to mean, for example, ringsystems such as cyclic amines such as azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl, azepinyl, morpholinyl or thiomorpholinyl, andin the case of the imides radicals such as pyrrolidine-2,5-dionyl,piperidine-2,6-dionyl, piperazine-2,6-dionyl, morpholine-3,5-dionyl, andin the case of the lactams radicals such as pyrrolidin-2-onyl,piperidin-2-onyl, piperazin-2-onyl, morpholin-3-onyl.

The rearranged expression “alkyl, alkylene or cycloalkyl some or all ofthe hydrogen atoms are replaced by fluorine” is understood to mean apartially fluorinated or perfluorinated alkyl, alkylene or cycloalkylwhich derives, for example, for alkyl from the following radicals:

—CF₃, —CHF₂, —CH₂F, —CHF—CF₃, —CHF—CHF₂,

—CHF—CH₂F, —CH₂—CF₃, —CH₂—CHF₂, —CH₂—CH₂F, —CF₂—CF₃, —CF₂—CHF₂,

—CF₂—CH₂F, —CH₂—CHF—CF₃, —CH₂—CHF—CHF₂, —CH₂—CHF—CH₂F,

—CH₂—CH₂—CF₃, —CH₂—CH₂—CHF₂, —CH₂—CH₂—CH₂F, —CH₂—CF₂—CF₃,

—CH₂—CF₂—CHF₂, —CH₂—CF₂—CH₂F, —CHF—CHF—CF₃, —CHF—CHF—CHF₂,—CHF—CHF—CH₂F, —CHF—CH₂—CF₃, —CHF—CH₂—CHF₂, —CHF—CH₂—CH₂F, —CHF—CF₂—CF₃,—CHF—CF₂—CHF₂, —CHF—CF₂—CH₂F, —CF₂—CHF—CF₃,

—CF₂—CHF—CHF₂, —CF₂—CHF—CH₂F, —CF₂—CH₂—CF₃, —CF₂—CH₂—CHF₂,—CF₂—CH₂—CH₂F, —CF₂—CF₂—CF₃, —CF₂—CF₂—CHF₂, —CF₂—CF₂—CH₂F, —CH(CF₃)₂,

—CH(CHF₂)₂, —CH(CFH₂)₂, —CH(CFH₂)(CHF₂), —CH(CFH₂)(CF₃), —CH(CFH₂)(CH₃),—CH(CHF₂)(CH₃), —CH(CF₃)(CH₃), —CF(CF₃)₂, —CF(CHF₂)₂, —CF(CFH₂)₂,—CF(CFH₂)(CHF₂), —CF(CFH₂)(CF₃), —CF(CFH₂)(CH₃), —CF(CHF₂)(CH₃), or

—CF(CF₃)(CH₃), and also the further possible combinations for butyl,pentyl and hexyl, which, like propyl, may also be branched,for alkylene, for example, from the following radicals: —CF₂—, —CHF—,—CHF—CF₂—, —CHF—CHF—, —CHF—CH₂—, —CF₂—CF₂— or —CF₂—CH₂F, and also thefurther possible combinations for propylene, butylene, pentylene andhexylene, which may also be branched, and for cycloalkyl, for example,from the radicals

and also the analogous larger cyclopentyl and cyclohexyl rings.

The expression “halogen” is understood to mean fluorine, chlorine,bromine or iodine, preference being given to fluorine, chlorine orbromine, especially to fluorine or chlorine.

The expressions described above can also be combined as desired, asdone, for example, in“—(C₀-C₆)-alkylene-O—(C₀-C₆)-alkylene-(C₆-C₁₄)-aryl”.

Functional groups of the intermediates used, for example amino orcarboxyl groups in the compound of the formula I, may be masked bysuitable protecting groups. Suitable protecting groups for aminofunctions are, for example, the t-butoxycarbonyl, the benzyloxycarbonylor the phthaloyl group, and also the trityl or tosyl protecting group.Suitable protecting groups for the carboxyl function are, for example,alkyl, aryl or arylalkyl esters. Protecting groups can be introduced andremoved by techniques which are well known or are described here (seeGreene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis(1999), 3rd Ed., Wiley-Interscience, or Kocienski, P. J., ProtectingGroups (2004), 3rd Ed., Thieme. The expression “protecting group” mayalso include corresponding polymer-bound protecting groups.

The inventive compounds can be prepared by well-known processes or byprocesses described here.

The invention further relates to a process for preparing the compound ofthe formula I and/or a stereoisomeric form of the compound of theformula I and/or a physiologically compatible salt of the compound ofthe formula I, which comprises

-   a) reacting a compound of the formula II

-   -   where R5, R6, R7, R8, R9, Q2 and Q3 are each as defined in        formula I and W is chloride, bromide, mesylate or tosylate with        a compound of the formula III

-   -   in which X, R2, R3 and R4 are each as defined in formula I, with        or without addition of base, in a solvent to give a compound of        the formula I, or

-   b) either isolating the compound of the formula I prepared by    method a) in free form or releasing it from physiologically    incompatible salts or, in the case of the presence of acidic or    basic groups, converting it to physiologically compatible salts, or

-   c) separating a compound of the formula I prepared by method a), or    a suitable precursor of the formula I which, owing to its chemical    structure, occurs in enantiomeric or diastereomeric forms, into the    pure enantiomers or diastereomers by salt formation with    enantiomerically pure acids or bases, chromatography on chiral    stationary phases or derivatization by means of chiral    enantiomerically pure compounds such as amino acids, separation of    the diastereomers thus obtained, and elimination of the chiral    auxiliary groups.

The invention further relates to a process for preparing the compound ofthe formula I according to scheme 1.

The reactants II and III, III optionally being present in the form of asalt, are converted at room temperature or a slightly elevatedtemperature from 40° C. to 60° C., advantageously, when III is in theform of a salt, in the presence of a base, preferably Hünig's base, in asolvent, preferably dimethylformamide (DMF) or dioxane, to give thecompound of the formula I. The X, A⁻, Q1, Q2, Q3, R2, R3, R4, R5, R6,R7, R8 and R9 radicals are each as defined in formula I, W represents agood leaving group such as chloride, bromide, mesylate or tosylate,preferably bromide or mesylate.

The 2-substituted triazolopyridazines (A) which are likewise formed indifferent proportions under these reaction conditions according to thesubstitution pattern can be removed by chromatography or bycrystallization. It is advantageous to separate by means of silica gelwith dichloromethane-methanol as the eluent mixture.

Hydrazines of the formula V type can be cyclized with cyano units of theZ—CN type to selectively form the 1-substituted cationic compounds ofthe formula I type where Q1 is hydrogen. Alternatively, it is possibleto cyclize the hydrazines of the formula V type with isothiocyanatesSCN-Q1′ of the formula XXV type selectively to the 1-substitutedcationic compounds of the formula I, in which case the thiourea formedas an intermediate can be cyclized with a “sulfur activator” such astosyl chloride, a carbodiimide, ethyl bromoacetate or mercury oxide togive compounds of the formula I type. In this case, the X, A⁻, Q1, Q2,Q3, R2, R3, R4, R5, R6, R7, R8 and R9 radicals are each as defined aboveand Q′ corresponds to Q1 or a protecting group such as FMOC(fluoren-9-ylmethyloxycarbonyl), which, after ring closure, can bedetached again, such that compounds where Q1 is hydrogen are obtainable.

Compounds of the formula II can be obtained commercially or byliterature methods, for example proceeding from the correspondingacetophenones X or X′ (see, for example: Phosphorus and Sulfur and theRelated Elements (1985), 25(3), 357 or Tetrahedron Letters (1984),25(34), 3715). The well-known compounds of the formula X type, which arecommercially available or can be synthesized in numerous structuralvariations, can, for example, be functionalized on the acetyl groupwith, among other reagents, elemental chlorine or bromine, tribromidederivatives such as phenyltrimethylammonium tribromide,1,3-dichlorodimethylhydantoin, N-chloro- or N-bromosuccinimide.Compounds of the formula X′ type can be converted, for example, usingmesyl or tosyl chloride to the compounds of the II type.

For particular R5 to R9 radicals, it may be more favorable first toconvert the ketones of the X type to the ketals of the XI or XI′ type,which can then be functionalized, preferably brominated, veryselectively on the methyl group to give the compounds of the XII type,and, after deketalization with suitable acids, likewise lead tocompounds of the II type.

The substituents in schemes 3 and 4 are each as defined above, T is a—(C₁-C₄)-alkyl group, while T′ is ethylene, propylene or butylene, W′ isa reactive compound such as phenyltrimethylammonium tribomide,N-bromosuccinimide or N-chlorosuccinimide.

Compounds of the formula III can be obtained commercially or byliterature methods. Suitable precursors are compounds of the XX type,which can be cyclized in the presence of cyanogen bromide, cyanogenchloride or tosyl cyanide to give compounds of the III type, and whichmay also be present in the tautomeric form of the XXa type.

The compound of the formula XX such as pyridazin-3-ylhydrazine and thecompound of the formula XXa such as [2H-pyridazin-(3E)-ylidene]hydrazineare tautomeric forms. When only one notation is utilized hereinafter,this means that the other tautomeric form is also disclosed.

The compound of the formula I can also be prepared in mesomeric formswhich derive from the following partial formulae of formula I:

The compound of the formula I can also be prepared in further mesomericforms which derive from the following partial formulae of formula Iwhen, for example, X is CH and R2 is OH:

It is also possible that the compound of the formula I forms an internalsalt because, for example, the Q1 radical, when it is —C(O)—O—CH₃ or—C(O)—CH₃, owing to its acidifying action, enables the formation of aninternal salt. An outwardly uncharged compound is therefore thenobtained, which does not require a counterion “A⁻”. This is also true ofthe nitrogen; here, the internal salt, in contrast to the form alreadydescribed, can rearrange to the neutral form. Acc is acceptor such ascarbonyl or else —CH₂CF₃.

Further mesomeric forms arise when the nitrogen cannot be stabilized bydeprotonation.

When only one notation is used in this application, this means that theother mesomeric forms are also disclosed too.

Alternatively, compounds of the XX type can also be reacted withisothiocyanates of the XXV type to given the thioureas of the XXVI type.The latter can, after activation of the sulfur, for example with ethylbromoacetate, a carbodiimide, tosyl chloride or mercury oxide, beconverted to the compounds of the formula III type. The X, R2, R3 and R4radicals here are each as defined above and Q1′ corresponds to Q1 or aprotecting group such as FMOC (fluoren-9-ylmethyloxycarbonyl), which,after ring closure, can be eliminated again, and so compounds where Q1is hydrogen are obtainable.

Compounds of the XX type can be obtained by incorporating hydrazine intocompounds of the XXI type, which are commercially available with a widevariety of different substitution patterns. The X, R2, R3 and R4radicals here are each as defined above and LG represents a good leavinggroup such as fluorine, chlorine, bromine, iodine, mesylate, tosylate,triflate or nonaflate.

One route to the chlorine compounds of the XXI′ type where X is nitrogenand R2 is chlorine is, for example, the reaction of maleic anhydrides ofthe XXIII type with hydrazine hydrochloride to give the compounds of theXXII type, followed by the reaction with phosphorus oxychloride to givethe dichloride XXI′ and with hydrazine to give the compounds of the XX′type where R2 is chlorine.

A compound of the formula I prepared according to scheme 1, or asuitable precursor of the formula I which, owing to its chemicalstructure, occurs in enantiomeric forms, can be separated into the pureenantiomers by salt formation with enantiomerically pure acids or bases,chromatography on chiral stationary phases or derivatization by means ofchiral enantiomerically pure compounds such as amino acids, separationof the diastereomers thus obtained, and elimination of the chiralauxiliary groups (process c), or the compound of the formula I preparedaccording to scheme 1 can either be isolated in free form or, in thecase of the presence of acidic or basic groups, converted tophysiologically compatible salts (process b).

Acidic or basic products of the compound of the formula I may be in theform of their salts or in free form. Pharmacologically acceptable saltsare preferred, for example alkali metal or alkaline earth metal salts orhydrochlorides, sulfates, hemisulfates, methylsulfonates,p-toluenesulfonates, all possible phosphates, and salts of amino acids,natural bases or carboxylic acids such as lactates, citrates, tartrates,acetates, adipates, fumarates, gluconates, glutamates, maleates orpamoates.

Physiologically tolerated salts are prepared from compounds of theformula I capable of salt formation, including their stereoisomericforms, in process step b) in a manner known per se. If compounds of theformula I contain acidic functionality, stable alkali metal, alkalineearth metal or optionally substituted ammonium salts can be formed withbasic reagents such as hydroxides, carbonates, bicarbonates, alkoxides,and ammonia or organic bases, for example trimethyl- or triethylamine,ethanolamine, diethanolamine or triethanolamine, trometamol or elsebasic amino acids, for instance lysine, ornithine or arginine. Basicgroups of the compounds of the formula I form acid addition salts withacids. Suitable for this purpose are both inorganic and organic acidssuch as hydrochloric or hydrobromic, sulfuric, hemisulfuric, phosphoric,methanesulfonic, benzenesulfonic, p-toluenesulfonic,4-bromobenzenesulfonic, cyclohexylamidosulfonic,trifluoromethylsulfonic, 2-hydroxyethanesulfonic, acetic, oxalic,tartaric, succinic, glycerolphosphoric, lactic, malic, adipic, citric,fumaric, maleic, gluconic, glucuronic, palmitic or trifluoroacetic acid.

In process step c), the compound of the formula I, if it occurs as amixture of diastereomers or enantiomers or results as mixtures thereofin the chosen synthesis, is separated into the pure stereoisomers eitherby chromatography on an optionally chiral support material or, if theracemic compound of the formula I is capable of salt formation, it isalso possible to carry out a fractional crystallization of thediastereomeric salts formed with an optically active base or acid asauxiliary. Examples of suitable chiral stationary phases for thin-layeror column chromatographic separation of enantiomers are modified silicagel supports (called Pirkle phases) and high molecular weightcarbohydrates such as triacetylcellulose. For analytical purposes it isalso possible to use gas chromatographic methods on chiral stationaryphases after appropriate derivatization known to the skilled worker. Toseparate enantiomers of the racemic carboxylic acids, the diastereomericsalts of differing solubility are formed with an optically active,usually commercially available, base such as (−)-nicotine, (+)- and(−)-phenylethylamine, quinine bases, L-lysine or L- and D-arginine, theless soluble component is isolated as solid, the more solublediastereomer is deposited from the mother liquor, and the pureenantiomers are obtained from the diastereomeric salts obtained in thisway. It is possible in the same way in principle to convert the racemiccompounds of the formula I which contain a basic group such an aminogroup, with optically active acids such as (+)-camphor-10-sulfonic acid,D- and L-tartaric acid, D- and L-lactic acid, and (+) and (−)-mandelicacid, into the pure enantiomers. It is also possible to convert chiralcompounds containing alcohol or amine functions with appropriatelyactivated or, where appropriate, N-protected enantiopure amino acidsinto the corresponding esters or amides, or conversely chiral carboxylicacids with carboxy-protected enantiopure amino acids into the amides orwith enantiopure hydroxy carboxylic acids such as lactic acid into thecorresponding chiral esters. The chirality of the amino acid or alcoholresidue which has been introduced in enantiopure form can then beutilized to separate the isomers by carrying out a separation of thediastereomers which are now available by crystallization orchromatography on suitable stationary phases, and then eliminating theincluded chiral moiety again by suitable methods.

A further possibility with some of the inventive compounds is to preparethe framework structures using diastereomerically or enantiomericallypure starting materials. It is thus possible also to employ other orsimplified processes for purifying the final products. These startingmaterials have previously been prepared enantiomerically ordiastereomerically pure by processes known from the literature. This maymean in particular that either enantioselective processes are employedin the synthesis of the basic structures, or else a separation ofenantiomers (or diastereomers) is carried out at an early stage of thesynthesis and not at the stage of the final products. A simplificationof these separations can likewise be achieved by proceeding in two ormore stages.

The invention also relates to medicaments having an effective content ofat least one compound of the formula I and/or a physiologicallytolerated salt of the compound of the formula I and/or an optionallystereoisomeric form of the compound of the formula I, together with apharmaceutically suitable and physiologically tolerated carrier,additive and/or other active ingredients and excipients.

Owing to the pharmacological properties, the compounds of the inventionare suitable for example for the prophylaxis, secondary prevention andtherapy of all disorders which can be treated by inhibition of theprotease-activated receptor 1 (PAR1). Thus, the compounds of theinvention are suitable both for a prophylactic and a therapeutic use onhumans. They are suitable both for acute treatment and for long-termtherapy. The compounds of the formula I can be employed in patientssuffering from impairments of well being or diseases associated withthromboses, embolisms, hypercoagulability, fibrotic changes orinflammatory disorders. These include myocardial infarction, anginapectoris and all other types of acute coronary syndrome, stroke,peripheral vascular disorders, deep vein thrombosis, pulmonary embolism,embolic or thrombotic events caused by cardiac arrhythmias,cardiovascular events such as restenosis following revascularization,angioplasty and similar procedures such as stent implantations andbypass operations. The compounds of the formula I can further beemployed in all procedures leading to contact of blood with foreignsurfaces, such as for dialysis patients and patients with indwellingcatheters. Compounds of the formula I can be employed in order to reducethe risk of thrombosis following surgical procedures such as knee andhip joint operations.

Compounds of the formula I are suitable for the treatment of patientswith disseminated intravascular coagulation, sepsis and otherintravascular events associated with inflammation. The compounds of theformula I are further suitable for the prophylaxis and treatment ofpatients with atherosclerosis, diabetes and the metabolic syndrome andthe sequelae thereof. Impairments of the hemostatic system (for examplefibrin deposits) have been implicated in mechanisms leading to tumorgrowth and tumor metastasis, and in inflammatory and degenerativearticular disorders such as rheumatoid arthritis and arthrosis.Compounds of the formula I are suitable for retarding or preventing suchprocesses.

Further indications for the use of the compounds of the formula I arefibrotic changes in the lung such as chronic obstructive pulmonarydisease, adult respiratory distress syndrome (ARDS) and of the eye suchas fibrin deposits following eye operations. Compounds of the formula Iare also suitable for the prevention and/or treatment of scarring.

The medicaments of the invention can be administered by oral,inhalational, rectal or transdermal administration or by subcutaneous,intraarticular, intraperitoneal or intravenous injection. Oraladministration is preferred. Coating of stents with compounds of theformula I and other surfaces which come into contact with blood in thebody is possible. The invention also relates to a process formanufacturing a medicament, which comprises making a suitable dosageform from at least one compound of the formula I with a pharmaceuticallysuitable and physiologically tolerated carrier and, where appropriate,further suitable active ingredients, additives or excipients.

Suitable solid or pharmaceutical formulations are, for example,granules, powder, coated tablets, tablets, (micro)capsules,suppositories, syrups, solutions, suspensions, emulsions, drops orinjectable solutions, and products with protracted release of activeingredient, in the production of which customary aids such as carriers,disintegrants, binders, coating agents, swelling agents, glidants orlubricants, flavorings, sweeteners and solubilizers are used. Excipientswhich are frequently used and which may be mentioned are magnesiumcarbonate, titanium dioxide, lactose, mannitol and other sugars, talc,milk protein, gelatin, starch, cellulose and its derivatives, animal andvegetable oils such as fish liver oil, sunflower, peanut or sesame oil,polyethylene glycol and solvents such as, for example, sterile water andmonohydric or polyhydric alcohols such as glycerol.

The pharmaceutical products are preferably manufactured and administeredin dosage units, where each unit comprises as active ingredient aparticular dose of the compound of the invention of the formula I. Inthe case of solid dosage units such as tablets, capsules, coated tabletsor suppositories, this dose can be up to about 1000 mg, but preferablyabout 50 to 300 mg and, in the case of injection solutions in ampouleform, up to about 300 mg but preferably about 10 to 100 mg.

The daily doses indicated for the treatment of an adult patient weighingabout 70 kg are, depending on the activity of the compound of formula I,from about 2 mg to 1000 mg of active ingredient, preferably about 50 mgto 500 mg. However, in some circumstances, higher or lower daily dosesmay also be appropriate. The daily dose can be administered either by asingle administration in the form of a single dosage unit or else aplurality of smaller dosage units or by multiple administration ofdivided doses at particular intervals.

Compounds of the formula I can be administered both as monotherapy andin combination or together with all antithrombotics (anticoagulants andplatelet aggregation inhibitors), thrombolytics (plasminogen activatorsof every type), other substances having profibrinolytic activity,antihypertensives, regulators of blood glucose, lipid-lowering agentsand antiarrhythmics. Suitable platelet aggregation inhibitors in thisconnection are cyclooxygenase 1 inhibitors such as aspirin, irreversibleP2Y₁₂ antagonists such as clopidogrel or prasugrel, reversible P2Y₁₂antagonists such as cangrelor or AZD6140 and thromboxaneA₂/prostaglandin H₂ antagonists such as terutroban. It has been possibleto show additive effects of PAR1 blockade in combination with P2Y₁₂blockade for example (Eur. Heart J. 2007, 28, Abstract Supplement, 188).

EXAMPLES

End products were generally characterized by a chromatographic methodwith ultraviolet and mass spectrometry detection (LCUV/ESI-MS coupling),and ¹H NMR. The compounds are described by reporting the correspondingretention time in the ion current (LC-MS rt) and the corresponding[M+H]⁺ signal in the case of positive ionization in the correspondingmass spectrum. When no [M+H]⁺ mass signal could be obtained, the ¹H NMRdata were reported as an alternative. Abbreviations used are eitherexplained or correspond to the usual conventions. Silica gel separationswere carried out manually (flash chromatography) or supported bysemiautomatic cartridge systems such as Companion (CombiFlash) orFlashmaster II (Jones Chromatography). Unless stated otherwise,chromatographic separations were carried out on silica gel with ethylacetate/heptane, dichloromethane/ethanol or dichloromethane/methanolmixtures as the eluent.

Solvents were evaporated generally under reduced pressure at from 35° C.to 45° C. on a rotary evaporator, which is referred to by phrases suchas “concentrated”, “concentrated by rotary evaporation”, “dried”, “freedof the solvent”, “solvent removed or drawn off” or similar expressions.

LCUV/MS analyses carried out under the following conditions:

Method a (=met. a)

System: Agilent 1100 HPLC-System coupled to 1100 LC/MSD Column: YMCJ'rshere ODS H80 20 × 2.1 mm, packing material 4 μm Eluent: ACN:H₂O +0.05% TFA (flow rate 1 ml/min) Gradient: 4:96 (0 min) → 95:5 (2 min) →95:5 (2.4 min) → 4:96 (2.45 min) Ionization: ESI⁺

Method B (=met. b):

System: Agilent 1200 HPLC-System coupled to 6120 LC/MS Column: Luna C18,10 × 2.0 mm, packing material 3 μm Eluent: ACN:H₂O + 0.05% TFA (flowrate 1.1 ml/min) Gradient: 7:93 (0 min) → 95:5 (1 min) → 95:5 (1.45 min)→ 7:93 (1.5 min) Ionization: ESI⁺

Method C (=met. c):

System: Agilent 1200 HPLC-System coupled to 6120 LC/MS Column: Luna C18,10 × 2.0 mm, packing material 3 μm Eluent: ACN:H₂O + 0.05% TFA (flowrate 1.1 ml/min) Gradient: 1:99 (0 min) → 7:93 (0.3 min) → 95:5 (1.3min) → 95:5 (1.75 min) → 1:99 (1.8 min) Ionization: ESI⁺

Method D (=met. d):

System: Waters: 1525 pump, 996 PDA, LCT classic TOF-MS Column: WatersXBridge C18 4.6 × 50 mm; 2.5 μM Eluent: ACN + 0.05% TFA:H₂O TFA (flowrate 1.3 ml/min), 40° C. Gradient: 5:95 (0 min) → 5:95 (0.3 min) → 95:5(3.5 min) → 95:5 (4 min) Ionization: ESI⁺

Method E (=met. e):

System: Waters: 1525 pump, 996 PDA, LCT classic TOF-MS Column: WatersXBridge C18; 4.6 × 50 mm; 2.5 μM Eluent: ACN + 0.05% TFA:H₂O TFA (flowrate 1.7 ml/min), 40° C. Gradient: 5:95 (0 min) → 5:95 (0.2 min) → 95:5(2.4 min) → 95:5 (3.2 min) → 5:95 (3.3 min) → 5:95 (4.0 min) Ionization:ESI⁺

Method F (=met. f):

System: Waters: 1525 pump, 996 PDA, LCT classic TOF-MS Column: YMCJ'shere, 33 × 2 mm, 4 μM Eluent: ACN + 0.05% TFA:H₂O + 0.05% TFA (flowrate 1.3 ml/min) Gradient: 5:95 (0 min) → 5:95 (2.5 min) → 95:5 (3 min)Ionization: ESI⁺

Preparative HPLC with reversed-phase (RP) silica gel was carried out bythe following methods:

Method A, standard method if no other method is mentioned in the text.

Column: Merck (Darmstadt, Deutschland) Purosphere ® RP18 25 × 250 mm, 10μm Eluent: ACN:H₂O + 0.05% TFA (flow rate 25 ml/min) Gradient: 10:90 (0min) → 90:10 (40 min)

Method B

Column: Merck Purosphere ® RP18 25 × 250 mm, 10 μm Eluent: ACN:H₂O +0.05% TFA (flow rate 25 ml/min) Gradient: 0:100 (0 min) → 0:100 (5 min)→ 20:80 (20 min)

Method C

Column: Agilent Prep-C18, 30 × 250 mm, 10 μm Eluent: ACN:H₂O + 0.05% TFA(flow rate 75 ml/min) Gradient: 10:90 (0 min) → 90:10 (12.5 min) → 90:10(15 min) → 10:90(15.5 min) → 10:90 (17.5 min)

The reactions took place in standard reaction apparatus such assingle-neck or multineck flasks, which, unless stated otherwise,according to the need, had a capacity of from 5 ml to 2000 ml and, asrequired, were equipped with a septum, stopper, condenser, stirrer orother equipment. Unless mentioned otherwise, all reactions took placeunder argon as protective gas and were stirred with magnetic stirrers.Microwave reactions were carried out in the Emrys Optimizer fromPersonal Chemistry in vessels of capacity from 0.5 to 10 ml according tothe need. Solvents such as dichloromethane, ethanol, dimethylformamide,methanol, isopropanol and the like were purchased as “dry” solvents andwere also used thus in the reactions, without this being explicitlymentioned in each case.

Abbreviations Used:

-   abs. absolute-   ACN acetonitrile-   Boc tert-butoxycarbonyl-   Ex. example-   DCM dichloromethane-   DIPEA N,N-diisopropylethylamine (Hünig's base)-   DMF dimethylformamide-   DMSO dimethyl sulfoxide-   EA ethyl acetate-   eq. equivalents-   EtOH ethanol-   h hour(s)-   HPLC high-performance liquid chromatography-   Hünig's base N,N-diisopropyl-N-ethylamine-   LC-MS rt retention time of the compound in the ion current of liquid    chromatography-   LCUV/MS ultraviolet liquid chromatography/mass spectrometry-   NMP 1-methyl-2-pyrrolidone-   MeOH methanol-   MtB ether tent-butyl methyl ether-   MW microwave-   RF reflux-   RT room temperature (20° C. to 25° C.)-   rt retention time-   TEA triethylamine-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TOTU    O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N′,N′-tetramethyluronium    tetrafluoroborate

Synthesis of the Units of the “Western Half” W1.0016-Ethoxy-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine

6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.001a, 616 mg) wasdissolved in absolute ethanol (40 ml) and admixed with portions of solidsodium ethoxide (990 mg). After stirring at 55° C. for 2 h, water wasadded and the aqueous phase was extracted three times withdichloromethane. The combined extracts were dried over sodium sulfate,filtered and concentrated. 709 mg of crude product of the desiredcompound were obtained in sufficient purity.

LC-MS rt: 0.51 min [M+H]⁺: 180.1 (met. a)

The following were synthesized analogously:

Number R LC-MS rt [M + H]⁺ Comment: W1.002 methyl- 0.22 166.1 (met. a)W2.001a (100 mg); sodium methoxide solution; product: 95 mg W1.003

0.69 194.1 (met. a) W2.001a (100 mg); sodium isopropoxide solution;product: 84 mg

W1.004 6-Cyclobutoxy-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine

Cyclobutanol (2.43 ml) was initially charged at RT with stirring andcooled almost to 0° C. with an ice bath. Subsequently, the mixture wasadmixed with portions of sodium hydride (146 mg). The suspension formedwas heated to 55° C. for 30 min and admixed with portions of6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.001,200 mg), suspended in cyclobutanol (5 ml). After stirring at 55° C. for1.5 h, the mixture was left to stand at RT overnight and then admixedwith water and extracted three times with dichloromethane. The combinedorganic phases were dried over sodium sulfate and, after the desiccanthad been filtered off, dried under reduced pressure. 136 mg of the titlecompound were obtained in solid form.

[LC-MS rt: 0.82 min [M+H]⁺: 206.2 (met. a)

The following units were synthesized analogously:

Number R LC-MS rt [M + H]⁺ Comment: W1.005

0.89 min 242.1 (met. a) W2.001a (100 mg) used dissolved in NMP; crudeproduct purified by chromatography using silica gel withdichloromethane/methanol gradient; product: 48 mg W1.006

0.95 min 234.1 (met. a) W2.001 (200 mg); Crude product purified bypreparative HPLC (met. A); product: 47 mg (TFA salt) W1.007

0.88 min 220.1 (met. a) W2.001 (463 mg); Crude product purified bypreparative HPLC (met. A); product: 15 mg (TFA salt) W1.008

0.92 min 222.1 (met. a) W2.001a (194 mg) used suspended in a mixture of10 ml of DMF and 5 ml of 3-pentanol; crude product purified bychromatography using silica gel with dichloromethane/methanol gradient;product: 155 mg

W1.009 6-Cyclopropylmethoxy-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine

Cyclopropylmethanol (2.64 ml) was initially charged in DMF (35 ml),admixed under argon with sodium hydride (795 mg) and stirred at 40° C.for 1 h. Subsequently,6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.001;1.66 g), dissolved in DMF (35 ml), were added dropwise. After 1 h, themixture was admixed with water and extracted by shaking four times withdichloromethane. The combined organic phases were dried over magnesiumsulfate and concentrated by rotary evaporation. The residue wastriturated with MtB ether, filtered off with suction and dried. 720 mgof the title compound were obtained.

LC-MS rt: 0.80 min [M+H]⁺: 206.1 (met. f)

The following units were synthesized analogously:

Number R LC-MS rt [min] [M + H]⁺ Comment: W1.010

0.91 208.2 (met. a) W2.001 (1.75 g); stirred al 45° C. for 1.5 h;product: 820 mg W1.011

0.63 254.1 (met. a) W2.001 (2.5 g); crude product purified by means of asilica gel cartridge (120 g, gradient; 0-20% dichloromethane/methanol in60 min); product: 1.08 g W1.012

0.52 210.1 (met. a) W2.001 (2.5 g); crude product purified by means of asilica gel cartridge (40 g, gradient; 0-20% dichloromethane/methanol in60 min); product: 1.04 g

W1.013 6-Phenoxy-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine

6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.001;200 mg) were initially charged dissolved in NMP (4 ml). Thereafter,sodium phenoxide (185 mg) was introduced at RT. After stirring at RT forone hour, the reaction was completed by heating to 55° C. for 2 h.Subsequently, the mixture was admixed with water and extracted threetimes with dichloromethane. The combined organic phases were dried oversodium sulfate and, after the desiccant had been filtered off, driedunder reduced pressure. The crude product was purified using silica gelwith a dichloromethane/methanol gradient. 38 mg of the title compoundwere obtained in solid form. LC-MS rt: 0.80 min [M+H]⁺: 228.1 (met. a)

W1.0146-(2,2,2-Trifluoroethoxy)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine

2,2,2-Trifluoroethanol (1 ml), sodium hydride (86 mg) and6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.001,100 mg) were reacted according to W1.004. 87 mg of the title compoundwere obtained in solid form.

LC-MS rt: 0.68 min [M+H]⁺: 234.1 (met. a)

W1.020 6-Piperidin-1-yl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine

6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.001;100 mg) were initially charged in water (1 ml) and admixed withpiperidine (260 μl) with stirring. Thereafter, the mixture was heated toreflux for 1 h and, after cooling, freed of the solvent. Subsequently,the mixture was admixed with water and the solid formed was filtered offwith suction and dried. The mother liquor was dried and admixed with alittle water. The solid obtained was filtered off with suction anddried. The filtrate was then extracted three times with dichloromethane.The combined organic phases were dried over sodium sulfate and, afterthe desiccant had been filtered off, dried under reduced pressure. Thethree resulting solid fractions were combined and gave rise to 56 mg ofthe title compound.

LC-MS rt: 0.77 min [M+H]⁺: 219.1 (met. a)

The following was prepared analogously:

Number LC-MS rt [M + H]⁺ Comment: W1.021

0.55 min 221.1 (met. a) W2.001 (150 mg); reflux for 5 h; dry crudeproduct admixed with water and extracted directly with DCM. product: 81mg

W1.022 N*6*,N*6*-Diethyl-[1,2,4]triazolo[4,3-b]pyridazine-3,6-diamine

6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.001;150 mg) was initially charged in water (5 ml) and admixed withdiethylamine (814 μl) while stirring. Thereafter, the mixture was heatedto reflux for 16 h and then further diethylamine (407 μl) was added.After refluxing for a further 12 h, the mixture was freed of thesolvent, admixed with water and extracted three times withdichloromethane. The combined organic phases were dried over sodiumsulfate and, after the desiccant had been filtered off, dried underreduced pressure. 67 mg of the title compound were obtained.

LC-MS rt: 0.72 min [M+H]⁺: 207.1 (met. a)

W1.025 6-Ethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine

(6-Ethylpyridazin-3-yl)hydrazine hydrochloride (2 g) was initiallycharged in a mixture of ethanol (30 ml) and water (6 ml) while stirringat RT. Thereafter, cyanogen bromide was cautiously added dropwise (2.4 gdissolved in 7.5 ml of ethanol and 1.5 ml of water). After stirring atRT for one hour, the mixture was left to stand overnight and, the nextday, stirred for 4 further hours. The solvent was then drawn off and theresidue was purified by means of preparative HPLC (met. C). The cleanproduct fractions were combined, freed of the acetonitrile under reducedpressure, alkalized with saturated potassium carbonate solution andextracted repeatedly with dichloromethane. The combined organic phaseswere dried over sodium sulfate, filtered and concentrated. 830 mg of thetitle compound were obtained.

The aqueous potassium carbonate phase was likewise freeze-dried, thentaken up with a little water and extracted five times withdichloromethane. The combined organic phases were dried over sodiumsulfate, filtered and concentrated. A further 180 mg of the titlecompound were obtained.

LC-MS rt: 0.32 min [M+H]⁺: 164.1 (met. a)

W1.0358-Methyl-6-(3-methyloxetan-3-ylmethoxy)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine

(3-Methyloxetan-3-yl)methanol (1.74 g) was initially charged in DMF (30ml), admixed under argon with sodium hydride (408 mg) and stirred at 45°C. for 0.5 h. Subsequently,6-chloro-8-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide(W2.002; 1.5 g) was dissolved in DMF (30 ml) and one equivalent of thealkoxide solution (10 ml) was added. After stirring at 45° C. for 30min, a further 0.5 equivalent of alkoxide solution was added, followedby 0.5 eq. each after a further 30 and 60 min. Then the mixture wasadmixed with water, and the reaction mixture was dried and purifiedusing silica gel (80 g cartridge, dichloromethane/methanol gradient of0-20% in 60 min). 758 mg of the title compound were obtained. LC-MS rt:0.49 min [M+H]⁺: 250.1 (met. b)

The following was prepared analogously:

Number LC-MS rt [M + H]⁺: Comment: W1.037

0.62 min 222.1 (met. a) W2.002 (1 g); product: 605 mg

W1.040N*6*,N*6*-Diethyl-8-methyl-[1,2,4]triazolo[4,3-b]pyridazine-3,6-diamine

6-Chloro-8-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide(W2.002; 250 mg) was dissolved in abs. DMF (2 ml) and admixed withdiethylamine (7 ml). Thereafter, the reaction mixture was placed into aheating block at 80° C. with stirring for 11 days. The solvent was thendrawn off and the residue was admixed with a little water and extractedthree times with dichloromethane. The combined organic phases were driedover sodium sulfate, filtered and concentrated. The residue was purifiedby means of preparative HPLC (met. A), and the clean product fractionswere combined, freed of the acetonitrile under reduced pressure,alkalized with saturated potassium carbonate solution and extractedrepeatedly with dichloromethane. The combined organic phases were driedover sodium sulfate, filtered and concentrated. 100 mg of the titlecompound were obtained.

LC-MS rt: 0.70 min [M+H]⁺: 221.2 (met. b)

W1.0717-Ethyl-6-(1-ethylpropoxy)-8-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine

3-Pentanol (2.5 ml) was initially charged at RT with stirring.Thereafter, sodium hydride (91 mg) was added while cooling with ice.After stirring at 55° C. for 2.5 h,6-chloro-7-ethyl-8-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine(W2.007; 120 mg), dissolved in 3-pentanol (2 ml) and DMF (4 ml), wasadded dropwise. After stirring for 1 h, the mixture was left to stand atRT overnight, and the reaction mixture was admixed with water anddichloromethane and then extracted three times with dichloromethane. Thecombined organic phases were dried over sodium sulfate and, after thedesiccant had been filtered off, dried under reduced pressure. 126 mg ofthe title compound were obtained.

LC-MS rt: 0.90 min [M+H]⁺: 264.2 (met. b)

W1.075 6-Ethoxy-8-ethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine

6-Chloro-8-ethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.003; 700mg) was dissolved in ethanol (100 ml) while stirring. Thereafter, thereaction mixture was admixed with sodium ethoxide (724 mg) and stirredat RT for 2 h. Subsequently, the mixture was heated to 45° C. for 3 h.After the solvent had been drawn off, the residue was admixed with waterand extracted three times with dichloromethane. The combined organicphases were dried over sodium sulfate and, after the desiccant had beenfiltered off, dried under reduced pressure. 670 mg of the title compoundwere obtained.

LC-MS rt: 0.64 min [M+H]⁺: 208.2 (met. b)

W1.085 6-Ethoxy-7-ethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine

6-Chloro-7-ethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylaminetrifluoroacetate salt (W2.011, 82 mg) was reacted and worked upanalogously to W1.075. 77 mg of the title compound were obtained. LC-MSrt: 0.69 min [M+H]⁺: 208.2 (met. b)

W1.100N,N-Diethyl-3-amino-6-ethoxy-[1,2,4]triazolo[4,3-b]pyridazine-7-carboxamide

N,N-Diethyl-3-amino-6-chloro-[1,2,4]triazolo[4,3-b]pyridazine-7-carboxamide(W2.019, 50 mg) was initially charged in ethanol (5 ml) and admixed withsodium ethoxide (28 mg) while stirring. After stirring at RT for 7 h andleaving to stand overnight, the solvent was drawn off and the mixturewas extracted three times with dichloromethane. The combined organicphases were dried over sodium sulfate and, after the desiccant had beenfiltered off, dried under reduced pressure. 51 mg of the title compoundwere obtained. LC-MS rt: 1.00 min [M+H]⁺: 279.2 (met. b)

W1.101N,N-Diethyl-3-amino-6-ethoxy-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxamide

N,N-Diethyl-3-amino-6-chloro-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxamide (W2.020, 50 mg) was prepared analogouslyto W1.100. 51 mg of the title compound were obtained. LC-MS rt: 1.04 min[M+H]⁺: 279.2 (met. b)

W1.1026-Ethoxy-N*7*,N*7*-diethyl-[1,2,4]triazolo[4,3-b]pyridazine-3,7-diamine

6-Chloro-N*7*,N*7*-diethyl-[1,2,4]triazolo[4,3-b]pyridazine-3,7-diamine(W2.021, 38 mg) were initially charged in ethanol (7 ml) and admixedwith sodium ethoxide (24 mg). The reaction mixture stirred at RT for 4h. It was then stirred at 45° C. for another 2 h. Subsequently, themixture was dried, the residue was admixed with water and extractedthree times with EA, and the combined EA phases were dried withmagnesium sulfate, filtered and concentrated. 30 mg of the titlecompound were obtained as a crude product, which was clean enough forthe next reaction.

LC-MS rt: 1.13 min [M+H]⁺: 251.2 (met. a)

W1.1076-(1-Ethylpropoxy)-8-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine

6-Chloro-8-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.009,80 mg) was reacted and worked up analogously to W1.071. The crudeproduct was then purified by means of preparative HPLC (met. A), and theclean product fractions were combined, freed of the acetonitrile underreduced pressure, alkalized with saturated potassium carbonate solutionand extracted repeatedly with dichloromethane. The combined organicphases were dried over sodium sulfate, filtered and concentrated. 51 mgof the title compound were obtained.

LC-MS rt: 0.91 min [M+H]⁺: 264.2 (met. b)

W1.1127-Ethyl-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine

6-Chloro-7-ethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.011, 150mg) was reacted, worked up and purified analogously to W1.107. 103 mg ofthe title compound were obtained.

LC-MS rt: 0.87 min [M+H]⁺: 250.2 (met. b)

W1.1136-(1-Ethylpropoxy)-7-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine

6-Chloro-7-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.013,100 mg) was reacted and worked up analogously to W1.071. 132 mg of thetitle compound were obtained, which was still contaminated with a littleDMF.

LC-MS rt: 0.90 min [M+H]⁺: 264.2 (met. b)

W1.1147-Cyclopropyl-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine

6-Chloro-7-cyclopropyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine(W2.012, 100 mg) was reacted and worked up analogously to W1.071. 116 mgof the title compound were obtained.

LC-MS rt: 0.87 min [M+H]⁺: 262.2 (met. b)

W1.125 6,7-Diethoxy-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine

(5,6-Diethoxy-pyridazin-3-yl)hydrazine (W3.120; 50 mg) was initiallycharged in a mixture of ethanol (3.5 ml) and water (0.75 ml) at RT whilestirring. Thereafter, cyanogen bromide (55 mg, dissolved in 0.75 ml ofethanol and 0.15 ml of water) was cautiously added dropwise. Afterstirring for 7 h, the mixture was left to stand overnight. Thereafter, afurther 2 equivalents of cyanogen bromide, dissolved in 0.75 ml ofethanol and 0.15 ml of water, were added and the mixture was stirredfurther at RT for 2 h and then at 55° C. for 8 h. After cooling, thesolvent was drawn off and the residue was admixed with water. After ithad been alkalized with saturated potassium carbonate solution, it wasextracted four times with dichloromethane. The combined organic phaseswere dried over sodium sulfate and, after the desiccant had beenfiltered off, dried under reduced pressure. The residue was purified bymeans of preparative HPLC (met. A). The clean product fractions werecombined, freed of the acetonitrile under reduced pressure, alkalizedwith saturated potassium carbonate solution and extracted four timeswith dichloromethane. The combined organic phases were dried over sodiumsulfate and, after the desiccant had been filtered off, dried underreduced pressure. 36 mg of the title compound were obtained. LC-MS rt:0.54 min [M+H]⁺: 224.2 (met. b)

W1.1306-Methanesulfonyl-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine

6-Chloro-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylaminehydrobromide (W2.006; 1.0 g) and sodium sulfinate (916 mg) weredissolved in DMF (6 ml) and stirred in a microwave at 150° C. for 45min. After the solvent had been drawn off, the residue was purifiedusing silica gel (40 g cartridge, dichloromethane/methanol gradient of0-20% in 60 min). 1.02 g of the title compound were obtained.

LC-MS rt: 0.33 min [M+H]⁺: 242.1 (met. b)

W1.1353-Amino-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine-6-carbonitrile

6-Methanesulfonyl-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W1.130;1.0 g) was dissolved in DMF (30 ml) and admixed with potassium cyanide(405 mg). After stirring at 100° C. for 1 h, the mixture was dried. Theresidue was stirred in EA and chromatographed using a short silica gelcolumn with EA. Fractions concentrated by rotary evaporation. 560 mg ofthe title compound were obtained.

LC-MS rt: 0.27 min [M+H]⁺: 189.1 (met. b)

W1.1403-Amino-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine-6-carboxylic acidhydrochloride

3-Amino-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine-6-carbonitrile(W1.135; 600 mg) was admixed with concentrated hydrochloric acid (20 ml)and kept at reflux for 5 h. Subsequently, the hydrochloric acid wasdrawn off, and the residue was taken up with water and freeze-dried. 790mg of the title compound were obtained, which was of sufficient purityfor the next reaction.

LC-MS rt: 0.19 min [M+H]⁺: 189.1 (met. c)

W1.145 Methyl3-amino-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine-6-carboxylatehydrochloride

3-Amino-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine-6-carboxylic acidhydrochloride (W1.140; 780 mg) was dissolved in methanol (40 ml) andthionyl chloride (1.9 ml) was slowly added dropwise, and then themixture was stirred at 65° C. After 2.5 h, the mixture was dried and theresidue was purified using silica gel (24 g cartridge,dichloromethane/methanol gradient of 0-20% in 60 min). 602 mg of thetitle compound were obtained.

LC-MS rt: 0.37 min [M+H]⁺: 222.1 (met. b)

W1.165(6-Ethoxy-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)(2,2,2-trifluoroethyl)amine

(6-Chloro-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)(2,2,2-trifluoroethyl)amine(W2.150; 330 mg) was initially charged in ethanol (25 ml) and admixedwith sodium ethoxide (90 mg). The reaction mixture was stirred at 50° C.for 4 h, then further sodium ethoxide (10 mg) was added and the mixturewas stirred further at 50° C. for 3 h. After standing overnight, themixture was admixed with water and dried. The residue was taken up in EAand washed three times with water. The EA phase was dried over sodiumsulfate, filtered and concentrated. 340 mg of the title compound wereobtained. LC-MS rt: 0.82 min [M+H]⁺: 290.2 (met. b)

The following were prepared analogously:

Number LC-MS rt [M + H]⁺ Comment: W1.166

0.75 min 248.2 (met. b) W2.166; 690 mg; product: 508 mg W1.168

0.78 min 250.2 (met. b) W2.168; 78 mg; product: 57 mg W1.169

0.71 min 222.2 (met. b) W2.169; 50 mg; product: 27 mg W1.170

0.49 min 208.2 (met. b) W2.170; 105 mg; product: 70 mg

W1.175[6-(1-Ethylpropoxy)-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]methylamine

3-Pentanol (1.2 ml) was initially charged at RT with stirring.Thereafter, sodium hydride (77 mg) was added while cooling with ice.After stirring at 55° C. for 3 h,(6-chloro-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylamine(W2.169; 50 mg), dissolved in 3-pentanol (1 ml) and DMF (2 ml), wasadded dropwise. After stirring for 2 h, the reaction mixture was left tostand at RT overnight, admixed with water and dichloromethane and thenextracted three times more with dichloromethane. The combined organicphases were dried over magnesium sulfate and, after the desiccant hadbeen filtered off, dried under reduced pressure. 44 mg of the titlecompound were obtained. LC-MS rt: 0.86 min [M+H]⁺: 264.2 (met. b)

The following was prepared analogously to W1.130:

W1.190

0.43 min 256.0 (met. b) W2.169 7.08 g; product: 4.84 g

The following was prepared analogously to W1.135:

W1.200

0.39 min 203.1 (met. b) W1.190 4.83 g; product: 3.50 g

The following was prepared analogously to W1.140:

W1.210

0.23 min 222.1 (met. c) W1.200 3.50 g; product: 5.27 g

The following was prepared analogously to W1.145:

LC-MS Number rt [M + H]⁺: Comment: W1.219

0.29 min 222.1 (met. b) W1.210 2.77 g; product: 2.56 g

W1.250N-Ethyl-7,8-dimethyl-3-methylamino-[1,2,4]triazolo[4,3-b]pyridazine-6-carboxamide

Methyl7,8-dimethyl-3-methylamino-[1,2,4]triazolo[4,3-b]pyridazine-6-carboxylatehydrochloride (W1.220; 1.3 g) was dissolved in methanol (30 ml), cooledto 0° C., slowly admixed dropwise with ethylamine (11.44 ml; 2 M in THF)and stirred at 0° C. for 6 h. Then four further equivalents ofethylamine were added and the mixture was left to stand at RT over theweekend. Subsequently, the mixture was concentrated and purified usingsilica gel (40 g cartridge, dichloromethane/methanol gradient of 0-20%in 60 min). 1.12 g of the title compound were obtained. LC-MS rt: 0.81min [M+H]⁺: 249.1 (met. b)

The following was prepared analogously:

Number LC-MS rt [M + H]⁺ Comment: W1.251

0.14 min 235.1 (met. b) W1.219; 770 mg; dimethylamine (5 + 2 eq.; 2M inTHF); product: 542 mg

W1.300 [1,2,4]Triazolo[4,3-a]pyridin-3-ylamine hydrobromide

2-Hydrazinopyridine (654 mg) was dissolved in a mixture of EtOH andwater (7.5/1.5 ml) at RT while stirring. Subsequently, cyanogen bromidesolution (666 mg dissolved in a mixture of EtOH/water 1.5/0.3 ml) wasadded dropwise while stirring. After stirring at RT for 6 h, the solventwas drawn off, and the residue was taken up in water and freeze-dried.1.3 g of the title compound were obtained. LC-MS rt: 0.15 min [M+H]⁺:135.3 (met. a)

W1.301 6-Trifluoromethyl-[1,2,4]triazolo[4,3-a]pyridin-3-ylaminehydrobromide and6-trifluormethyl-[1,2,4]triazolo[4,3-a]pyridin-3-ylamine

5-(Trifluoromethyl)pyrid-2-ylhydrazine (500 mg) was dissolved at RT in amixture of EtOH/water (7.5/1.5 ml) while stirring. Thereafter, cyanogenbromide solution (314 mg dissolved in EtOH/water 0.75/0.15 ml) wasslowly and cautiously added dropwise within 30 min. After stirring at RTfor 3 h, the precipitate was filtered off with suction and dried underhigh vacuum (oil pump). 329 mg of6-trifluoromethyl-[1,2,4]triazolo[4,3-a]pyridin-3-ylamine hydrobromidewere obtained.

The mother liquor was dried and the residue was purified by means ofpreparative HPLC. The clean, product-containing fractions were combinedand freed of the ACN, and the aqueous residue was alkalized withsaturated sodium hydrogencarbonate solution. Then the residue wasextracted three times with EA and the combined EA phases were dried overmagnesium sulfate, filtered and concentrated. 110 mg oftrifluoromethyl-[1,2,4]triazolo[4,3-a]pyridin-3-ylamine were obtained.

LC-MS rt 0.54 min [M+H]⁺: 203.1 (met. a)

W2 W2.001 6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylaminehydrobromide

3-(Chlorpyridazin-6-yl)hydrazine (5 g) was dissolved in a mixture ofEtOH (90 ml) and water (36 ml) at RT while stirring. Thereafter, 5 Mcyanogen bromide solution (13 ml in acetonitrile) was cautiously addeddropwise. After stirring for 4.5 h, the mixture was left to standovernight and, the next day, further 5 M cyanogen bromide solution (3 mlin acetonitrile) was added while stirring. After a further 4 h ofstirring, the precipitate formed was filtered off with suction anddried. 6.1 g of the title compound were obtained.

The mother liquor was admixed with MtB ether and the precipitate formedwas filtered off with suction and dried, so as to obtain a further 1.5 gof the title compound.

LC-MS rt: 0.24 min [M+H]⁺: 170.1 (met. a)

W2.001a 6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine

6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.001;1.1 g) was taken up with a large amount of water and alkalized withsaturated potassium carbonate solution. The solid which precipitated outwas filtered off with suction and dried (388 mg). Repeated extraction ofthe mother liquor with dichloromethane, drying of the combined organicphases over sodium sulfate, filtration and concentration afforded afurther 228 mg of product in total.

LC-MS rt: 0.24 min [M+H]⁺: 170.1 (met. a)

W2.002 6-Chloro-8-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylaminehydrobromide

(6-Chloro-4-methylpyridazin-3-yl)hydrazine (W3.002; 4.6 g) wereinitially charged in EtOH (330 ml) and water (70 ml) while stirring atRT. Thereafter, cyanogen bromide in a mixture of EtOH (170 ml) and water(30 ml) was slowly added dropwise at RT. After stirring at RT for 6 h,the mixture was left to stand overnight. Then the mixture was dried andthe residue was purified using silica gel (40 g cartridge, DCM/methanolgradient of 0-10% in 30 min). 7.3 g of the title compound were obtained.

LC-MS rt: 0.17 min [M+H]⁺: 184.1 (met. b)

W2.002b 6-Chloro-8-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylaminetrifluoroacetic acid salt

(6-Chloro-4-methylpyridazin-3-yl)hydrazine (W3.002; 432 mg) wasinitially charged in a mixture of ethanol (15 ml) and water (3 ml) whilestirring at RT. Thereafter, cyanogen bromide (581 mg, dissolved in 7 mlof EtOH and 1.5 ml of water) was cautiously added dropwise. Afterstirring for 2 h, the mixture was left to stand overnight. Thereafter,the mixture was stirred at RT for a further 4 h and then at 50° C. for 2h. After cooling overnight, the solvent was drawn off and the residuewas purified by means of preparative HPLC (met. A). The clean productfractions were combined, freed of the acetonitrile under reducedpressure and freeze-dried. 158 mg of the title compound were obtained.

LC-MS rt: 0.44 min [M+H]⁺: 184.1 (met. a)

W2.0076-Chloro-7-ethyl-8-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine

(6-Chloro-5-ethyl-4-methylpyridazin-3-yl)hydrazine (W3.007; 340 mg) wasdissolved in ethanol/water (10/2 ml) at RT while stirring. Thereafter,cyanogen bromide (386 mg, dissolved in 5 ml of ethanol and 1 ml ofwater) was cautiously added dropwise. After stirring at RT for 5 h, themixture was left to stand overnight and then the solvent was drawn off,and the residue was admixed with water. Once the residue had beenalkalized with saturated potassium carbonate solution, it was extractedthree times with dichloromethane. The combined organic phases were driedover sodium sulfate and, after filtering off the desiccant, dried underreduced pressure. 385 mg of the title compound were obtained. LC-MS rt:0.62 min [M+H]⁺: 212.1 (met. b)

W2.0086-Chloro-8-ethyl-7-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine

(6-Chloro-4-ethyl-5-methylpyridazin-3-yl)hydrazine trifluoroacetic acidsalt (W3.008; 340 mg) was initially charged in a mixture of EtOH (12 ml)and water (2 ml) at RT while stirring. Thereafter, cyanogen bromide (240mg), dissolved in 3 ml of EtOH and 1 ml of water, was cautiously addeddropwise and the mixture was stirred for 8 h. After standing overnight,0.5 eq. cyanogen bromide solution was added and the mixture was stirredagain at RT for 4.5 h and then at 55° C. for 2 h. After standingovernight, the solvent was drawn off and the residue was admixed withwater. Once it had been alkalized with saturated potassium carbonatesolution, the mixture was extracted three times with dichloromethane.The combined organic phases were dried over sodium sulfate and, afterthe desiccant had been filtered off, dried under reduced pressure. 270mg of the title compound were obtained.

LC-MS rt: 0.54 min [M+H]⁺: 212.1 (met. b)

W2.009 6-Chloro-8-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine

(6-Chloro-4-isopropylpyridazin-3-yl)hydrazine trifluoroacetic acid salt(W3.009; 258 mg) was initially charged in ethanol/water (6/1 ml) at RTwhile stirring. Thereafter, cyanogen bromide (182 mg, dissolved in amixture of 1.5 ml of EtOH and 0.5 ml of water) was cautiously addeddropwise. After stirring for 5 hours, the mixture was left to standovernight, another 1 eq. of the cyanogen bromide solution was added andthe mixture was stirred all day. After standing overnight, the solventwas drawn off and the residue was admixed with water. Once the residuehad been alkalized with saturated potassium carbonate solution, it wasextracted three times with dichloromethane. The combined organic phaseswere dried over sodium sulfate and, after filtering off the desiccant,dried under reduced pressure. 180 mg of the title compound were obtainedin sufficient purity. LC-MS rt: 0.65 min [M+H]⁺: 212.1 (met. b)

¹H NMR (500 MHz, DMSO-d6) [ppm]: 6.98 (1H), 6.63 (2H), 3.37 (1H), 1.35(6H)

W2.011 6-Chloro-7-ethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine

(6-Chloro-5-ethylpyridazin-3-yl)hydrazine trifluoroacetic acid salt(W3.011; 169 mg) was converted and worked up analogously to W2.009. 130mg of the title compound were obtained in sufficient purity.

LC-MS rt: 0.33 min [M+H]⁺: 198.1 (met. b)

W2.012 6-Chloro-7-cyclopropyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine

(6-Chloro-5-cyclopropylpyridazin-3-yl)hydrazine trifluoroacetic acidsalt (W3.012; 400 mg) was converted and worked up analogously to W2.008,except that, instead of 0.5, one further equivalent of cyanogen bromidesolution was added. 260 mg of the title compound were obtained insufficient purity.

LC-MS rt: 0.45 min [M+H]⁺: 210.1 (met. b)

W2.013 6-Chloro-7-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine

(6-Chloro-5-isopropylpyridazin-3-yl)hydrazine trifluoroacetic acid salt(W3.013; 400 mg) was initially charged in ethanol/water (6/1 ml) at RTwhile stirring. Thereafter, cyanogen bromide (353 mg, dissolved in amixture of 1 ml of EtOH and 0.5 ml of water) was cautiously addeddropwise. After stirring for 5 hours, the mixture was left to standovernight and stirred for a further day. After standing overnight, thesolvent was drawn off and the residue was admixed with water. Once theresidue had been alkalized with saturated potassium carbonate solution,it was extracted three times with dichloromethane. The combined organicphases were dried over sodium sulfate and, after filtering off thedesiccant, dried under reduced pressure. 400 mg of the title compoundwere obtained in sufficient purity.

LC-MS rt: 0.65 min [M+H]⁺: 212.1 (met. b)

¹H NMR (500 MHz, DMSO-d6) [ppm]: 7.97 (1H), 6.61 (2H), 3.11 (1H), 1.25(6H)

W2.019N,N-Diethyl-3-amino-6-chloro-[1,2,4]triazolo[4,3-b]pyridazine-7-carboxamide

N,N-Diethyl-3-chloro-6-hydrazinopyridazine-4-carboxamide trifluoroaceticacid salt (W3.019; 390 mg) was converted and worked up analogously toW2.007. 285 mg of the title compound were obtained in sufficient purity.

LC-MS rt: 0.94 min [M+H]⁺: 269.1 (met. a)

W2.020N,N-Diethyl-3-amino-6-chloro-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxamide

N,N-Diethyl-6-chloro-3-hydrazinopyridazine-4-carboxamide trifluoroaceticacid salt (W3.020; 320 mg) was converted and worked up analogously toW2.007. 222 mg of the title compound were obtained in sufficient purity.

LC-MS rt: 0.93 min [M+H]⁺: 269.1 (met. a)

W2.0216-Chloro-N*7*,N*7*-diethyl-[1,2,4]triazolo[4,3-b]pyridazine-3,7-diamine

(3-Chloro-6-hydrazinopyridazin-4-yl)diethylamine (W3.021; 215 mg) wasconverted analogously to W2.007, and the solvent mixture was drawn off.The residue was purified by means of preparative HPLC (met. A). Theproduct fractions, each of them clean, were combined, freed of theacetonitrile under reduced pressure, adjusted to pH 9 with sodiumhydrogencarbonate and extracted five times with DCM. The combinedorganic phases were dried over magnesium sulfate and, after filteringoff the desiccant, dried under reduced pressure. 94 mg of the titlecompound were obtained in sufficient purity.

LC-MS rt: 1.04 min [M+H]⁺: 241.1 (met. a)

W2.150(6-Chloro-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-(2,2,2-trifluoroethyl)amine

N*-(6-Chloro-4,5-dimethylpyridazin-3-yl)amino-N-(2,2,2-trifluoroethyl)urea(W3.150; 400 mg) was dissolved in phosphorus oxychloride (10 ml) andheated to 80° C. while stirring. After stirring at 80° C. for 7 h, themixture was left to stand overnight and then the phosphorus oxychloridewas drawn off. The residue was dissolved in water/DCM and adjusted to pH9 with sodium hydrogencarbonate, and the phases were separated. Theaqueous phase was extracted three times with DCM, and the combinedextracts were washed with saturated sodium chloride solution, dried oversodium carbonate, filtered and concentrated. 330 mg of the titlecompound were obtained.

LC-MS rt: 0.83 min [M+H]⁺: 280.1 (met. b)

The following were prepared analogously to W2.169:

Number LC-MS rt [M + H]⁺ Comment: W2.166

0.64 min 238.1 (met. b) W3.166 830 mg; purification by means of HPLC(met. D); product: 690 mg W2.168

0.68 min 226.1 (met. b) W3.168 140 mg; purification by means of HPLC(met. D); product: 82 mg

W2.169(6-Chloro-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylaminehydrobromide

N′-(6-Chloro-4,5-dimethylpyridazin-3-yl)amino-N-methylthiourea (W3.169;11.25 g) was dissolved in ethanol (400 ml), admixed with ethylbromoacetate (5.57 ml) and kept under reflux with exclusion of moisture.After 2 h, the solvent was drawn off and the residue was purified usingsilica gel (120 g cartridge, DCM/methanol gradient of 0-10% in 60 min).10.9 g of the title compound were obtained. LC-MS rt: 0.35 min [M+H]⁺:212.1 (met. b)

The following was prepared analogously to W2.169:

Number LC-MS rt [M + H]+: Comment: W2.170

0.24 min 198.1 (met. b) W3.170 7.74 g; product: 7.93 g

W3 W3.002 (6-Chloro-4-methylpyridazin-3-yl)hydrazine

Synthesized analogously to U.S. Pat. No. 4,578,464

LC-MS rt: 0.21 min [M+H]⁺: 159.1 (met. a)

W3.003 and W3.011 (6-Chloro-4-ethylpyridazin-3-yl)hydrazinetrifluoroacetate and (6-chloro-5-ethylpyridazin-3-yl)hydrazinetrifluoroacetate

3,6-Dichloro-4-ethylpyridazine (W4.003, 2×2.4 g) was divided between 2microwave vessels and each was admixed with a mixture of hydrazinemonohydrate (6 ml) and dioxane (7 ml). The reaction mixture was kept inthe microwave at 130° C. for 1 h. Subsequently, the contents of the twovessels were combined in a round-bottom flask and dried. The residue wasadmixed with water and extracted three times with dichloromethane. Thecombined organic phases were dried over sodium sulfate and, after thedesiccant had been filtered off, dried under reduced pressure. Theworkup process was repeated twice more. The residue thus obtained wasseparated by means of preparative HPLC (method A, except gradient of100% water+0.05% TFA→15% acetonitrile/85% water+0.05% TFA in 25 min).The product fractions, each of them clean, were combined, freed of theacetonitrile under reduced pressure and freeze-dried. 1.35 g of(6-chloro-4-ethylpyridazin-3-yl)hydrazine as the trifluoroacetate and3.96 g of (6-chloro-5-ethylpyridazin-3-yl)hydrazine as thetrifluoroacetate were obtained.

-   (6-Chloro-4-ethylpyridazin-3-yl)hydrazine as the trifluoroacetate,    W3.003

LC-MS rt: 0.20 min [M+H]⁺: 173.1 (met. c)

-   (6-Chloro-5-ethylpyridazin-3-yl)hydrazine as the trifluoroacetate,    W3.011

LC-MS rt: 0.13 min [M+H]⁺: 173.1 (met. b)

W3.005 (6-Chloro-5-methylpyridazin-3-yl)hydrazine

Synthesized analogously to U.S. Pat. No. 4,578,464 LC-MS rt: 0.26 min[M+H]⁺: 159.1 (met. a)

W3.006 (6-Chloro-4,5-dimethylpyridazin-3-yl)hydrazine

3,6-Dichloro-4,5-dimethylpyridazine (W4.006; 29.0 g) was admixed with160 ml of hydrazine monohydrate solution (160 ml) and heated to 90° C.while stirring for 4 h. The reaction mixture was admixed with water andthe precipitate was filtered off with suction, washed with water anddried over phosphorus pentoxide. 27.2 g of the title compound wereobtained.

LC-MS rt: 0.15 min [M+H]⁺: 173.1 (met. b)

W3.007 and W3.008 (6-Chloro-5-ethyl-4-methylpyridazin-3-yl)hydrazine(also as the TFA salt) and(6-chloro-4-ethyl-5-methylpyridazin-3-yl)hydrazine trifluoroacetic acidsalt

3,6-Dichloro-4-ethyl-5-methylpyridazine (W4.007; 1 g) was initiallycharged in dioxane (8 ml) with addition of hydrazine monohydrate (2 ml)in a microwave vessel at RT. Thereafter, the reaction mixture was keptat 140° C. in the microwave for 1 h. In the course of standingovernight, a solid precipitated out, which was filtered off withsuction, washed and dried. 345 mg of(6-chloro-5-ethyl-4-methylpyridazin-3-yl)hydrazine were obtained as thefree base.

The mother liquor was concentrated to dryness and the residue waspurified by means of preparative HPLC (met. F). The product fractions,each of them clean, were combined, freed of the acetonitrile underreduced pressure and freeze-dried. 340 mg of6-chloro-4-ethyl-5-methylpyridazin-3-yl)hydrazine trifluoroacetic acidsalt and 239 mg of (6-chloro-5-ethyl-4-methylpyridazin-3-yl)hydrazine asthe trifluoroacetate were obtained.

-   (6-Chloro-5-ethyl-4-methylpyridazin-3-yl)hydrazine trifluoroacetic    acid salt, W3.007

LC-MS rt: 0.25 min [M+H]⁺: 187.1 (met. b)

-   (6-Chloro-4-ethyl-5-methylpyridazin-3-yl)hydrazine trifluoroacetic    acid salt, W3.008

LC-MS rt: 0.22 min [M+H]⁺: 187.1 (met. b)

W3.009 and W3.013 (6-Chloro-4-isopropylpyridazin-3-yl)hydrazinetrifluoroacetic acid salt and(6-chloro-5-isopropylpyridazin-3-yl)hydrazine trifluoroacetic acid salt

3,6-Dichloro-4-isopropylpyridazine (W4.009; 2.3 g) was convertedanalogously to W3.007 and then dried. After preparative chromatography(met. F), 260 mg of (6-chloro-4-isopropylpyridazin-3-yl)hydrazinetrifluoroacetic acid salt and 2.16 g of(6-chloro-5-isopropylpyridazin-3-yl)hydrazine trifluoroacetic acid saltwere obtained.

-   (6-Chloro-4-isopropylpyridazin-3-yl)hydrazine trifluoroacetic acid    salt, W3.009

LC-MS rt: 0.20 min [M+H]⁺: 187.1 (met. b)

-   (6-Chloro-5-isopropylpyridazin-3-yl)hydrazine trifluoroacetic acid    salt, W3.012

LC-MS rt: 0.34 min [M+H]⁺: 187.1 (met. b)

W3.010 and W3.012 (6-Chloro-4-cyclopropylpyridazin-3-yl)hydrazinetrifluoroacetic acid salt and(6-chloro-5-cyclopropylpyridazin-3-yl)hydrazine trifluoroacetic acidsalt

3,6-Dichloro-4-cyclopropylpyridazine (W4.010; 1.4 g) was convertedanalogously to W3.007 and then dried. After preparative chromatography(met. F), 805 mg of (6-chloro-4-cyclopropylpyridazin-3-yl)hydrazinetrifluoroacetic acid salt and 708 mg of(6-chloro-5-cyclopropylpyridazin-3-yl)hydrazine were obtained.

-   (6-Chloro-4-cyclopropylpyridazin-3-yl)hydrazine trifluoroacetic acid    salt, W3.010

LC-MS rt: 0.15 min [M+H]⁺: 185.1 (met. b)

-   (6-Chloro-5-cyclopropylpyridazin-3-yl)hydrazine trifluoroacetic acid    salt, W3.012

LC-MS rt: 0.22 min [M+H]⁺: 185.1 (met. b)

W3.019 and W3.020N,N-Diethyl-3-chloro-6-hydrazinopyridazine-4-carboxamide trifluoroaceticacid salt and N,N-diethyl-6-chloro-3-hydrazinopyridazin-4-carboxamidetrifluoroacetic acid salt

N,N-Diethyl-3,6-dichloropyridazine-4-carboxamide (W4.019; 18 g) wassuspended in water (60 ml) and admixed with hydrazine monohydrate (2.8ml). After stirring at 60° C. for 1 h, the mixture was heated to 100° C.for 2 h. After cooling to RT, the mixture was admixed with DCM andextracted four times with DCM. The combined extracts were dried oversodium sulfate, filtered and concentrated. The residue was purified bymeans of preparative HPLC (met. C). The clean, product-containingfractions were each combined, freed of ACN and freeze-dried. 910 mg ofN,N-diethyl-3-chloro-6-hydrazinopyridazine-4-carboxamide trifluoroaceticacid salt and 560 mg ofN,N-diethyl-6-chloro-3-hydrazinopyridazine-4-carboxamide trifluoroaceticacid salt were obtained.

-   N,N-Diethyl-3-chloro-6-hydrazinopyridazine-4-carboxamide    trifluoroacetic acid salt

LC-MS rt: 0.79 min [M+H]⁺: 244.1 (met. a)

-   6-Chloro-3-hydrazinopyridazine-4-carboxamide trifluoroacetic acid    salt

LC-MS rt: 0.68 min [M+H]⁺: 244.1 (met. a)

W3.021 (3-Chloro-6-hydrazinopyridazin-4-yl)diethylamine trifluoroaceticacid salt

(3,6-Dichloropyridazin-4-yl)diethylamine (W4.021; 500 mg) was initiallycharged in dioxane (20 ml) while stirring, and admixed with hydrazinehydrate (0.65 ml). Thereafter, the mixture was heated first at 80° C.for 2 h and then to reflux for 3 h. After being left to stand over theweekend, the mixture was heated to reflux for a further 48 h and, aftercooling, the solvent was drawn off. The residue was purified by means ofpreparative HPLC (met. A). The clean, product-containing fractions wereeach combined, freed of the ACN, basified with saturated sodiumhydrogencarbonate solution and then extracted five times with EA andfive times with DCM. The combined organic phases were dried overmagnesium sulfate, filtered and concentrated. 118 mg of reactant and 220mg of the title compound were isolated.

LC-MS rt: 1.24 min [M+H]⁺: 220.1 (met. a)

W3.120 (5,6-Diethoxypyridazin-3-yl)hydrazine

N-(5,6-Diethoxypyridazin-3-yl)-N-nitroamine (W4.120; 114 mg) wasdissolved in acetic acid (5 ml) and added dropwise while cooling withice and stirring at between 10 and 20° C. to a mixture of zinc (130 mg)in water (3 ml). Thereafter, the ice bath was removed and the mixturewas stirred at RT for 1 h. Then the mixture was alkalized with 10 Nsodium hydroxide solution, the aqueous phase was extracted three timeswith DCM, and the combined DCM phases were dried over sodium sulfate,filtered and concentrated. The residue was purified by means ofpreparative HPLC (met. A). The clean, product-containing fractions wereeach combined, freed of the ACN, basified with saturated potassiumcarbonate solution and then extracted three times with DCM. The combinedorganic phases were dried over sodium sulfate, filtered andconcentrated. 50 mg of the title compound were obtained.

LC-MS rt: 0.37 min [M+H]⁺: 199.2 (met. b)

W3.150N*-(6-Chloro-4,5-dimethylpyridazin-3-yl)amino-N-(2,2,2-trifluoroethyl)ureaandN*-(6-chloro-4,5-dimethylpyridazin-3-yl)amino-N-(2,2,2-trifluorethyl)ureahydrochloride

4-Nitrophenyl chloroformate (750 mg) was dissolved in THF (55 ml),2,2,2-trifluoroethylamine (0.3 ml) was added while stirring and themixture was stirred at RT for 3 h. Then(6-chloro-4,5-dimethylpyridazin-3-yl)hydrazine (W3.006, 620 mg) wasadded dissolved in THF (100 ml), followed by triethylamine (0.7 ml), andstirred at RT for 3 h. After being left to stand overnight, theprecipitated solid was filtered off with suction and dried. 840 mg ofthe free base were obtained, which still contained significant amountsof triethylamine hydrochloride.

The mother liquor was dried and purified by means of preparative HPLC(met. D). The clean, product-containing fractions were combined anddried. A further 400 mg of the title compound were obtained as thehydrochloride. LC-MS rt: 0.40 min [M+H]⁺: 298.1 (met. b)

W3.166N*-(6-Chloro-4,5-dimethylpyridazin-3-yl)amino-N-(cyclopropyl)thiourea

6-Chloro-4,5-dimethylpyridazin-3-yl)hydrazine (W3.006, 540 mg) wasdissolved in methylene chloride (50 ml), and cyclopropyl isothiocyanate(290 μl) was added while stirring. The mixture was stirred at RT for 7 hand then left to stand overnight. Thereafter, it was admixed withdiethyl ether (50 ml) and stirred for 3 h, and the precipitate formedwas filtered off with suction. The precipitate was washed with ether anddried under reduced pressure. 830 mg of the title compound wereobtained.

LC-MS rt: 0.62 min [M+H]⁺: 272.1 (met. b)

W3.167N*-(6-Chloro-4,5-dimethylpyridazin-3-yl)amino-N-(isopropyl)thiourea

6-Chloro-4,5-dimethylpyridazin-3-yl)hydrazine (W3.006, 380 mg) wasreacted with isopropyl isothiocyanate (235 μl) and worked up analogouslyto W3.166. The precipitate obtained was 428 mg. The mother liquor wasdried and purified using silica gel (70 g cartridge, DCM/methanolgradient 0-30% within 30 min). This afforded a further 119 mg ofproduct.

LC-MS rt: 0.78 min [M+H]⁺: 274.1 (met. b)

W3.168 N*-(6-Chloro-5-methylpyridazin-3-yl)amino-N-(isopropyl)thiourea

6-Chloro-5-dimethylpyridazin-3-yl)hydrazine as the trifluoroacetic acidsalt (W3.005, 660 mg) was dissolved in DCM (55 ml), while stirring withisopropyl isothiocyanate (258 μl) and triethylamine (310 ml) was added.Workup and isolation were effected analogously to the method describedin W3.167. In this case, 140 mg of the title compound were isolated as aprecipitate. LC-MS rt: 0.81 min [M+H]⁺: 260.1 (met. b)

W3.169 N′-(6-Chloro-4,5-dimethylpyridazin-3-yl)amino-N-methylthiourea

(6-Chloro-4,5-dimethylpyridazin-3-yl)hydrazine (W3.006; 8.00 g) wasdissolved in DCM (400 ml) and admixed with methyl isothiocyanate (3.39g). Subsequently, the mixture was stirred at RT for 24 h and left tostand over the weekend. The precipitate was filtered off, washed withDCM and dried in a drying cabinet at 45° C. 11.25 g of the titlecompound were obtained.

LC-MS rt: 0.29 min [M+H]+: 246.1 (met. b)

W3.170 N′-(6-Chloro-4-methylpyridazin-3-yl)amino-N-methylthiourea

(6-Chloro-4-methylpyridazin-3-yl)hydrazine (W3.002; 5.5 g) was reactedand worked up analogously to W3.169. However, stirring was carried outfor three days instead of one. 7.75 g of the title compound wereobtained.

LC-MS rt: 0.20 min [M+H]⁺: 232.1 (met. b)

W4 W4.003 and W4.014 3,6-Dichloro-4-ethylpyridazine and3,6-dichloro-4,5-diethylpyridazine

In analogy to: Samaritoni, Org. Prep. Proc. Int. 117 (1988)

3,6-Dichloropyridazine (10 g), silver nitrate (5.7 g) and propionic acid(7.5 ml) were initially charged in water (125 ml) and, at 50° C.,concentrated sulfuric acid (11 ml) was added dropwise. After theaddition, the reaction mixture was heated to 60° C. and a solution ofammonium persulfate (46 g) in water (125 ml) was slowly added dropwisewithin 20 min. After the addition, the mixture was heated to 70° C. for30 min. After standing overnight, the reaction mixture was poured ontoice/water and adjusted to pH7 with 25% ammonium hydroxide solution. Thenthe mixture was extracted three times with dichloromethane. The combinedorganic phases were dried over sodium sulfate and, after the desiccanthad been filtered off, dried under reduced pressure. The residue waspurified by means of preparative HPLC (met. C). The product fractions,each of them clean, were combined, freed of the acetonitrile underreduced pressure and extracted three times with dichloromethane. Thecombined organic phases were dried over sodium sulfate and, after thedesiccant had been filtered off, dried under reduced pressure. 6.6 g of3,6-dichloro-4-ethylpyridazine and 3.0 g of3,6-dichloro-4,5-diethylpyridazine were obtained.

-   3,6-Dichloro-4-ethylpyridazine, W4.003

LC-MS rt: 0.83 min [M+H]⁺: 177.1 (met. b)

-   3,6-Dichloro-4,5-diethylpyridazine, W4.014

LC-MS rt: 1.02 min [M+H]⁺: 205.1 (met. b)

W4.006 3,6-Dichloro-4,5-dimethylpyridazine

4,5-Dimethyl-1,2-dihydropyridazine-3,6-dione (W5.006; 69.7 g) wassuspended in phosphorus oxychloride (150 ml) and heated to 80° C. for 2h. After cooling, the mixture was added to ice-water and adjustedcautiously to pH 10 with 10 M NaOH while cooling with ice. Theprecipitate was filtered off with suction, washed with water and dried.78.3 g of the title compound were obtained.

LC-MS rt: 0.63 min [M+H]⁺: 177.1 (met. b)

W4.009 and W4.015 3,6-Dichloro-4-isopropylpyridazine and3,6-dichloro-4,5-diisopropylpyridazine

The compound was synthesized analogously to W4.003. 2.5 g of3,6-dichloropyridazine and isobutyric acid (2.34 ml) were used to obtain2.46 g of 3,6-dichloro-4-isopropylpyridazine and 0.33 g of3,6-dichloro-4,5-diisopropylpyridazine.

-   3,6-Dichloro-4-isopropylpyridazine, W4.009

LC-MS rt: 0.96 min [M+H]⁺: 191.1 (met. b)

-   3,6-Dichloro-4,5-diisopropylpyridazine, W4.015

LC-MS rt: 1.14 min [M+H]⁺: 233.1 (met. b)

W4.010 and W4.016

3,6-Dichloro-4-cyclopropylpyridazine and3,6-dichloro-4,5-dicyclopropylpyridazine

The compound was synthesized analogously to W4.003. 3 g of3,6-dichloropyridazine and cyclopropanecarboxylic acid (2.41 ml) wereused to obtain 1.6 g of 3,6-dichloro-4-cyclopropylpyridazine and 0.96 gof 3,6-dichloro-4,5-dicyclopropylpyridazine.

-   3,6-Dichloro-4-cyclopropylpyridazine, W4.010

LC-MS rt: 0.87 min [M+H]⁺: 189.1 (met. b)

-   3,6-Dichloro-4,5-dicyclopropylpyridazine, W4.016

LC-MS rt: 1.05 min [M+H]⁺: 229.1 (met. b)

W4.019 N,N-Diethyl-3,6-dichloropyridazine-4-carboxamide

3,6-Dichloropyridazine-4-carbonyl chloride (2.5 g) was initially chargedin DCM (25 ml) at RT. Thereafter, diethylamine (1.5 ml) predissolved inDCM (5 ml) was slowly added dropwise while stirring. After stirring atRT for 3 h, the mixture was admixed with water and extracted three timeswith DCM. The combined DCM phases were dried over sodium sulfate,filtered and concentrated. The residue was purified by means of silicagel (70 g cartridge, n-heptane/EA gradient). 1.8 g of the title compoundwere obtained.

LC-MS rt: 0.97 min [M+H]⁺: 248.1 (met. a)

W4.021 (3,6-Dichloropyridazin-4-yl)diethylamine

3,4,6-Trichloropyridazine (2 g) and diethylamine (2.4 ml) were initiallycharged in toluene (10 ml) and left to stand at RT for 3 days. Then themixture was admixed with water and EA, and the EA phase was removed. TheEA phase was washed three times with water, dried over magnesiumsulfate, filtered and concentrated. The residue was purified usingsilica gel (70 g cartridge, n-heptane/EA gradient 0-50% within 60 min).1.1 g of the title compound were obtained.

LC-MS rt: 1.24 min [M+H]⁺: 248.1 (met. a)

W4.120 N-(5,6-Diethoxypyridazin-3-yl)-N-nitroamine

5,6-Diethoxypyridazin-3-ylamine (analogously to T. Horie in Chemical &Pharmaceutical Bulletin (1963), 11(9), 1157-67; 160 mg) was initiallycharged dissolved in concentrated sulfuric acid (4 ml) at RT. Themixture was then cooled to 0° C. and 2 ml of a 1:1 mixture ofconcentrated nitric acid and concentrated sulfuric acid were addeddropwise. After 20 min at 0° C., the ice bath was removed and themixture was stirred for 4 h. Then it was cooled again to 0° C., afurther 0.5 ml of the acid mixture was added and the mixture was stirredat 0° C. for another hour. Then it was admixed with ice while coolingwith ice. After adding DCM, the phases were separated and extractedthree times with DCM. The combined DCM phases were dried over sodiumsulfate, filtered and concentrated. 188 mg of the title compound wereobtained. LC-MS rt: 0.81 min [M+H]⁺: 236.2 (met. b)

W5 W5.006 4,5-Dimethyl-1,2-dihydropyridazine-3,6-dione

Hydrazine dihydrochloride (83.6 g) was dissolved in water (20 ml) andheated to 100° C., and 3,4-dimethylfuran-2,5-dione (100.4 g) wasintroduced while stirring. Then the mixture was heated to reflux for 3h. Subsequently, the precipitate formed was filtered off with suction,washed with water and dried. The residue was suspended in EA (2 l),filtered off with suction and dried. 69.7 g of the title compound wereobtained. LC-MS rt: 0.19 min[M+H]+: 141.1 (met. b)

Synthesis of the units of the “eastern half”

O1.001 N-[3-(2-Bromoacetyl)-5-(pentafluorosulfanyl)phenyl]acetamide

N-[3-Acetyl-5-(pentafluorosulfanyl)phenyl]acetamide (859 mg, forsynthesis see example 1) was dissolved in a mixture of methanol (10 ml)and THF (10 ml) and phenyltrimethylammonium tribromide (1.065 g) wasadded in portions while stirring. After stirring at RT for 2 h, themixture was heated to 40° C. for a further 3 h. After cooling, thereaction mixture was added to 2 N sulfuric acid and the aqueous phasewas extracted 3 times with ethyl acetate. The combined extracts weredried over sodium sulfate, filtered and concentrated. The crude productwas purified using silica gel with ethyl acetate/heptane as the eluent.480 mg of the desired compound were obtained. LC-MS rt: 1.47 min [M+H]⁺:382.0 (met. a)

O1.002 2-Bromo-1-(3,5-di-tert-butyl-4-hydroxyphenyl)ethanone (ApolloScientific)

O1.003 2-Bromo-1-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)ethanone

Prepared as described in WO 2004/078721.

O1.0042-Bromo-1-(4-methoxy-3-morpholin-4-yl-5-trifluoromethylphenyl)ethanone

4-[5-(1,1-Dimethoxyethyl)-2-methoxy-3-trifluormethylphenyl]morpholine(O2.004; 460 mg) was dissolved in a mixture of methanol (1.4 ml) and THF(4 ml), the mixture was cooled to 7° C., and phenyltrimethylammoniumtribromide (530 mg) was added in portions while stirring. After stirringat RT for 3 h, the mixture was left to stand overnight. Then aqueousthiosulfate solution (0.8 ml; w=5%) and water (4 ml) were added, and themixture was admixed with EA and extracted three times with EA. Thecombined extracts were dried over magnesium sulfate, filtered andconcentrated. The residue was dissolved in a mixture of acetonitrile (20ml) and water (0.5 ml) and admixed with TFA (0.5 ml) while stirring.After stirring at RT for 5 h, the solvent was drawn off, and the residuewas admixed with water, neutralized with saturated sodiumhydrogencarbonate solution and extracted three times with ethyl acetate.The combined extracts were dried over magnesium, filtered andconcentrated. The crude product was purified using silica gel with ethylacetate/heptane as the eluent. 200 mg of the desired compound wereobtained.

LC-MS rt: 1.67 min [M+H]⁺: 382.0 (met. a)

O1.006 2-Bromo-1-[3-methylamino-5-(pentafluorosulfanyl)phenyl]ethanone

N-[3-(2-Bromoacetyl)-5-(pentafluorosulfanyl)phenyl]-2,2,2-trifluoro-N-methylacetamide (O1.075; 1.2 g) wasadmixed with water (15 ml), and concentrated sulfuric acid (15 ml) wasadded dropwise while stirring and with ice cooling. The mixture washeated to 80° C. and stirred at this temperature for 7 h. After cooling,the reaction mixture was added slowly to a mixture of 10 N sodiumhydroxide solution and EA, and the aqueous phase was extracted fivetimes with EA. The combined organic phases were dried over magnesiumsulfate and, after the desiccant had been filtered off, dried underreduced pressure. The residue was purified by means of preparative HPLC(met. A). The product fractions, each of them clean, were combined,freed of the acetonitrile under reduced pressure, neutralized withsodium hydrogencarbonate and extracted three times with EA. The combinedorganic phases were dried over magnesium sulfate and, after thedesiccant had been filtered off, dried under reduced pressure. 420 mg ofthe title compound were isolated.

LC-MS rt: 1.64 min [M+H]⁺: 354.0 (met. a)

O1.007 2-Bromo-1-[3-methoxy-5-(pentafluorosulfanyl)phenyl]ethanone

1-[3-Methoxy-5-(pentafluorosulfanyl)phenyl]ethanone (O2.007; 1.63 g) wasdissolved in THF (150 ml), and phenyltrimethylammonium tribromide (2.2g) was added at RT while stirring. After stirring at RT for 2 h, themixture was admixed with water, neutralized with sodiumhydrogencarbonate solution and extracted three times with EA. Thealkaline water phase was extracted 3× with EA. The combined organicphases were dried over magnesium sulfate and, after the desiccant hadbeen filtered off, dried under reduced pressure. The residue waspurified by means of preparative HPLC (met. A). The product fractions,each of them clean, were combined, freed of the acetonitrile underreduced pressure, neutralized with sodium hydrogencarbonate andextracted three times with EA. The combined organic phases were driedover magnesium sulfate and, after the desiccant had been filtered off,dried under reduced pressure. 1.27 g of the title compound wereisolated. LC-MS rt: 1.65 min [M+H]⁺: 354.9 (met. b)

O1.008 2-Bromo-1-(3-tert-butyl-5-ethoxymethylphenyl)ethanone

1-(3-tert-Butyl-5-ethoxymethylphenyl)ethanone (O2.008; 550 mg) wasdissolved in methanol/THF (10 ml/10 ml), admixed withphenyltrimethylammonium tribromide (882 mg) while stirring and stirredat RT for 2 h. Subsequently, the reaction mixture was poured onto DCM(200 ml) and washed thoroughly once with 5% sodium thiosulfate solutionand once with water. Then the DCM phase was dried and concentrated. Theresidue was purified using silica gel (40 g cartridge, n-heptane/EAgradient of 0-50% in 30 min). 566 mg of the title compound wereobtained. LC-MS rt: 1.83 min [M+H]⁺: 313.2 (met. a)

The following were prepared analogously:

Number LC-MS rt [M + H]⁺ Comment: O1.009

1.92 min 339.2 (met. a) O2.009; 595 mg; product: 691 mg O1.010

2.01 min 343.2 (met. a) O2.010; 410 mg; product: 405 mg O1.011

1.77 min 299.2 (met. a) O2.011; 390 mg; 5% citric acid solution addedinstead of thiosulfate; product: 387 mg O1.012

1.94 min 327.2 (met. a) O2.012; 333 mg; stirred at RT for 12 h; stirredwith 20% citric acid solution instead of thiosulfate solution 1 h;product: 327 mg O1.013

2.16 min 395.3 (met. a) O2.013; 540 mg; after thiosulfate solution,washed additionally with 20% citric acid solution; product: 600 mg

O1.014 2-Bromo-1-(3-methoxy-5-trifluoromethylphenyl)ethanone

1-(3-Methoxy-5-trifluormethylphenyl)ethanone (O2.014, 50 mg) wasdissolved in DCM (0.8 ml) and added dropwise at RT to a mixture ofcopper(II) bromide (102 mg) in EA (1.2 ml). After heating to RT for 2 h,the mixture was left to stand overnight, then the reaction mixture wasfiltered through “Celite” and washed thoroughly with EA, and thefiltrate was dried. The residue was taken up with EA and semisaturatedsodium hydrogencarbonate solution and then extracted twice with EA. Thecombined EA phases were washed with semisaturated sodiumhydrogencarbonate solution, dried over sodium sulfate, filtered andconcentrated. The crude product was purified by means of preparativeHPLC (met. A). The product fractions, each of them clean, were combined,freed of the acetonitrile under reduced pressure and extracted threetimes with EA. The combined organic phases were dried over sodiumsulfate and, after the desiccant had been filtered off, dried underreduced pressure. 39 mg of the title compound were isolated.

LC-MS rt: 1.64 min [M+H]⁺: 297.0 (met. a)

The following were prepared analogously to O1.008:

Number LC-MS rt [M + H]⁺ Comment: O1.015

1.77 min 285.1 (met. a) O2.015; 880 mg; 5% citric acid solution addedinstead of thiosulfate solution; product; 327 mg O1.016

1.97 min 325.1 (met. a) O2.016; 1.02 g; stirred with 5% citric acidsolution for 2 h instead of thiosulfate solution; product: 1.23 g O1.017

2.14 min 339.2 (met. a) O2.017; 25 mg; stirred with 5% citric acidsolution for 2 h instead of thiosulfate solution; product: 314 mg O1.018

2.18 min 389.3 (met. a) O2.018; 638 mg; stirred with 5% citric acidsolution for 2 h instead of thiosulfate solution; product: 809 mg O1.019

1.94 min 371.3 (met. a) O2.019; 360 mg; after thiosulfate solution,washed additionally with 20% citric acid solution; product: 261 mgO1.020

1.72 min 299.1 (met. a) O2.020; 1.53 g; after thiosulfate solution,washed additionally with 20% citric acid solution; product: 1.04 gO1.021

1.58 min  262.9/ 265.0 (met. a) O2.021; 41 g; after thiosulfatesolution, washed additionally with 20% citric acid solution; product:572 mg

O1.0222-Bromo-1-(8-tert-butyl-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)ethanone

1-(8-tert-Butyl-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)ethanone(250 mg, purchased from Chembiotek, India) was heated to from 50° C. to55° C. in a mixture of acetic acid (4 ml) and toluene (8 ml). At thistemperature, bromine (200 mg dissolved in acetic acid) was cautiouslyadded dropwise. After 2.5 h, the heating was removed, and the mixturewas admixed at RT with ice-water and extracted three times with toluene.The combined organic phases were dried over sodium sulfate, filtered andconcentrated. The crude product was purified using silica gel, so as toobtain 65 mg of the desired compound, as well as a further 43 mg ofproduct which was slightly contaminated and 37 mg of reactant.

LC-MS rt: 1.81 min [M+H]⁺: 326.0 (met. a)

O1.030 2-Bromo-1-(3-isopropyl-5-methoxyphenyl)ethanone

1-(3-Isopropyl-5-methoxyphenyl)ethanone (O2.030; 425 mg) was dissolvedin methanol/THF 15 ml/15 ml) and admixed while stirring withphenyltrimethylammonium tribromide (831 mg). After stirring at RT for 3h, the reaction mixture was added to 50 ml of 20% citric acid andstirred for 1 h. After adding water and EA, the EA phase was removed,dried and concentrated. The residue was dissolved in acetonitrile (50ml), and 2 N sulfuric acid (15 ml) was added to the solution. Afterstanding at RT for 2 h, the mixture was admixed with water and extractedwith EA. The EA phase was washed with saturated sodium hydrogencarbonatesolution, dried and concentrated. The residue was purified using silicagel (40 g cartridge, n-heptane/EA gradient of 0-50% within 30 min). 520mg of the title compound were obtained.

LC-MS rt: 1.65 min [M+H]⁺: 271.1 (met. a)

O1.031 2-Bromo-1-(3-cyclohexylmethoxy-5-ethoxyphenyl)ethanone

Proceeding from 1-(3-cyclohexylmethoxy-5-ethoxyphenyl)ethanone (O2.031,1.76 g), the title compound was prepared analogously to O1.008. Forfurther purification, however, the silica gel chromatography wasfollowed by a further purification by means of preparative HPLC. 370 mgof the title compound were obtained.

LC-MS rt: 2.11 min [M+H]⁺: 355.1 (met. a)

O1.032 2-Bromo-1-(3-bromo-5-methoxyphenyl)ethanone

1-(3-Bromo-5-methoxyphenyl)ethanone (O2.032, 1.45 g) was dissolved inmethanol/THF (40 ml/40 ml) and admixed while stirring withphenyltrimethylammonium tribromide (2.38 g). After stirring at RT for 24h, water and EA were added. The EA phase was removed, dried andconcentrated. The residue was dissolved in acetonitrile (50 ml), and 2 Nsulfuric acid (15 ml) was added to the solution. After standing at RTfor 1 h, the mixture was admixed with water and extracted twice with EA.The EA phase was washed with saturated sodium hydrogencarbonatesolution, dried and concentrated. The residue was purified using silicagel (40 g cartridge, n-heptane/EA gradient of 0-50% within 30 min. 1.39g of the title compound were obtained.

¹H NMR (500 MHz, DMSO-d6) [ppm]: 7.71 (1H), 7.48 (2H), 4.97 (2H), 3.84(3H)

O1.034 2-Bromo-1-[3-(3,3-dimethylbutoxy)-5-ethoxyphenyl]ethanone

Proceeding from 1-[3-(3,3-dimethylbutoxy)-5-ethoxyphenyl]ethanone(O2.034; 950 mg), the title compound was obtained analogously to O1.031.236 mg of the title compound were obtained, which was still somewhatcontaminated.

LC-MS rt: 2.06 min [M+H]⁺: 343.2 (met. a)

O1.035 2-Bromo-1-(3-cyclohexylmethoxy-5-methoxyphenyl)ethanone

1-(3-Cyclohexylmethoxy-5-methoxyphenyl)ethanone (O2.035; 1.33 g) wasconverted analogously to O1.032. However, the mixture was stirred at RTonly for 3 h instead of 24. 950 mg of the title compound were obtained.LC-MS rt: 2.03 min [M+H]⁺: 341.2 (met. a)

O1.041 2-Bromo-1-(5-bromo-2,3-dimethoxyphenyl)ethanone

1-(5-Bromo-2,3-dimethoxyphenyl)ethanone (O2.041; 1.1 g) was convertedanalogously to O1.032. 1.21 g of the title compound were obtained.

LC-MS rt: 1.62 min [M+H]⁺: 337.0 (met. a)

O1.042 2-Bromo-1-(3-chloro-4,5-dimethoxyphenyl)ethanone

1-(3-Chloro-4,5-dimethoxyphenyl)ethanone (O2.042; 490 mg) was convertedanalogously to O1.032. 577 mg of the title compound were obtained.

LC-MS rt: 1.54 min [M+H]⁺: 293.0 (met. a)

O1.043 2-Bromo-1-[3-tert-butyl-5-(2-methoxyethoxy)phenyl]ethanone

1-[3-tert-Butyl-5-(2-methoxyethoxy)phenyl]ethanone (O2.043; 1 g) wasdissolved in methanol/THF (25 ml/25 ml), admixed withphenyltrimethylammonium tribromide (882 mg) while stirring and stirredat RT overnight. Then 50 ml of 20% citric acid solution were added andthe mixture was stirred for 1 h. Subsequently, DCM (200 ml) was addedand the mixture was extracted three times with DCM. Then the combinedDCM phases were dried over magnesium sulfate, filtered and concentrated.The residue was purified using silica gel (40 g cartridge, n-heptane/EAgradient of 0-30% in 30 min). 1.31 g of the title compound wereobtained.

LC-MS rt: 1.72 min [M+H]⁺: 329.2 (met. a)

O1.0442-Bromo-1-[3-morpholin-4-yl-5-(pentafluorosulfanyl)phenyl]ethanone

1-[3-Morpholin-4-yl-5-(pentafluorosulfanyl)phenyl]ethanone (O2.044; 1.1g) was dissolved in methanol/THF (20/20 ml) and admixed while stirringwith phenyltrimethylammonium tribromide (1.25 g). After stirring at RTfor 27 h, 50 ml of 20% citric acid were added and the mixture wasstirred for 1 h. After adding DCM (100 ml), the DCM phase was removed,dried and concentrated. The residue was dissolved in acetonitrile (100ml), and 2 N sulfuric acid (20 ml) was added to the solution. Afterstirring at RT for 24 h, the mixture was admixed with water andextracted with EA. The EA phase was washed with saturated sodiumhydrogencarbonate solution, dried and concentrated. The residue waspurified using silica gel (80 g cartridge, n-heptane/EA gradient of0-60% within 40 min). 866 mg of the title compound were obtained. LC-MSrt: 1.69 min [M+H]⁺: 410.0 (met. a)

O1.061 2-Bromo-1-[3-tert-butyl-5-(2-hydroxyethoxy)phenyl]ethanone

1-{3-tert-Butyl-5-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}ethanone(O2.061; 3.9 g) was dissolved in methanol/THF (60 ml/60 ml) and admixedwhile stirring with phenyltrimethylammonium tribromide (5.03 g). Afterstirring at RT for 3 h, the mixture was added to 20% citric acid andstirred for 1 h. After adding EA, the EA phase was removed, dried andconcentrated. The residue was purified using silica gel (80 g cartridge,n-heptane/EA gradient of 0-50% within 60 min). 2.56 g of the titlecompound were obtained.

LC-MS rt: 0.90 min [M+H]⁺: 315.0 (met. b)

Number LC-MS rt [M + H]⁺ Comment:: O1.070

0.96 min 345.1 (met. b) Synthesis analogous to O1.071: O2.070 NUF3.153:6.68 g; product: 3.3 g NUF3.154

O1.0712-Bromo-1-[3-tert-butyl-5-(3-hydroxypropoxy)-4-methoxyphenyl]ethanone

1-{3-tert-Butyl-4-methoxy-5-[3-(tetrahydropyran-2-yloxy)propoxy]phenyl}ethanone(O2.071; 12.7 g) was dissolved in methanol/THF (200/200 ml) and admixedwith phenyltrimethylammonium tribromide (13.1 g) while stirring. Themixture was stirred at RT for 1 h, then diluted with DCM and washed oncewith 5% sodium thiosulfate solution. The DCM phase was dried overmagnesium sulfate, filtered and concentrated. The residue was taken upin acetonitrile (100 ml) and admixed with 48% hydrobromic acid (5.91ml). The mixture was left to stand for 1 h, then admixed with water,extracted by shaking with EA, and the combined EA phases were dried overmagnesium sulfate, filtered and concentrated. The residue was purifiedusing silica gel (120 g cartridge, n-heptane/MtB ether gradient of0-100% in 60 min). 3.29 g of the title compound were obtained.

LC-MS rt: 1.01 min [M+H]⁺: 359.1 (met. b)

O1.075N-[3-(2-Bromoacetyl)-5-(pentafluorosulfanyl)phenyl]-2,2,2-trifluoro-N-methylacetamide

N-[3-Acetyl-5-(pentafluorosulfanyl)phenyl]-2,2,2-trifluoro-N-methylacetamide(O2.075; 1.03 g) was dissolved in a mixture of methanol (20 ml) and THF(20 ml). Phenyltrimethylammonium tribromide (1.05 g) was added whilestirring. After stirring at RT for 5 h, the mixture was left to standovernight, then further phenyltrimethylammonium tribromide (100 mg) wasadded and the mixture was heated to 60° C. for 2 h. After cooling, thereaction mixture was added to 2 N sulfuric acid and stirred for 10 min.Then the aqueous phase was extracted three times with EA. The combinedorganic phases were dried over magnesium sulfate and, after thedesiccant had been filtered off, dried under reduced pressure. 1.2 g ofthe title compound were obtained, which had sufficient purity for thenext reactions.

LC-MS rt: 1.72 min [M+H]⁺: 449.9 (met. a)

O2.0044-[5-(1,1-Dimethoxyethyl)-2-methoxy-3-trifluoromethylphenyl]morpholine

1-Bromo-5-(1,1-dimethoxyethyl)-2-methoxy-3-trifluoromethylbenzene(O3.004; 700 mg) was initially charged in dioxane (7 ml) and admixedsuccessively with Pd(II) acetate (46 mg), cesium carbonate (2 g),9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (118 mg) and morpholine(0.27 ml). Thereafter, the reaction mixture was heated to 90° C. for 7 hand then left to stand overnight. Subsequently, it was filtered and thefiltrate was concentrated by rotary evaporation. The residue waspurified using silica gel (50 g cartridge, n-heptane/EA gradient). 433mg of the title compound were obtained.

LC-MS rt: 1.55 min [M+H]⁺: 304.0 (met. a)

O2.007 1-[3-Methoxy-5-(pentafluorosulfanyl)phenyl]ethanone

3,N-Dimethoxy-N-methyl-5-(pentafluorosulfanyl)benzamide (O3.007; 2.0 g)was dissolved in absolute THF (60 ml), and methylmagnesium bromide (5.2ml, 3 M in diethyl ether) was added dropwise at 0° C. while stirring.After addition, the ice bath was removed and the mixture was stirred atRT for 2 h. 1 N hydrochloric acid was then added dropwise while cooling,followed by water and ethyl acetate. The organic phase was removed andthe aqueous phase was extracted twice more with ethyl acetate. Thecombined extracts were dried over magnesium sulfate, filtered andconcentrated. The residue was purified by means of preparative HPLC(met. A). The product-containing fractions were combined, freed of theacetonitrile and extracted three times with ethyl acetate. The combinedextracts were dried over magnesium sulfate, filtered and concentrated.1.63 g of the desired compound were obtained.

¹H NMR (400 MHz, DMSO-d6) [ppm]: 7.87 (1H), 7.75 (1H), 7.67 (1H), 3.91(3H), 2.64 (3 H)

O2.008 1-(3-tert-Butyl-5-ethoxymethylphenyl)ethanone

3-tert-Butyl-N-methoxy-5-methoxymethyl-N-methylbenzamide (O3.008; 854mg) was converted analogously to O2.043. 550 mg of the title compoundwere obtained.

LC-MS rt: 1.70 min [M+H]⁺: 235.3 (met. a)

O2.009 1-(3-tert-Butyl-5-cyclopropylmethoxymethylphenyl)ethanone

Proceeding from methyl 3-tert-butyl-5-hydroxymethylbenzoate andcyclopropylmethyl bromide, the title compound (600 mg) was preparedanalogously to O5.008 to O2.008.

LC-MS rt: 1.81 min [M+H]⁺: 261.2 (met. a)

O2.010 1-(3-tert-Butyl-4,5-diethoxyphenyl)ethanone

1-(3-tert-Butyl-4-ethoxy-5-hydroxyphenyl)ethanone (O3.010; 470 mg) andethyl iodide (193 μl) were dissolved in DMF (6.2 ml), and sodium hydride(57 mg) was added. After stirring at RT for 0.5 h, the DMF was drawn offand the residue was taken up in EA, washed with water, dried andconcentrated. The residue was purified using silica gel (40 g cartridge,n-heptane/EA gradient 0-30% within 60 min). 420 mg of the title compoundwere obtained. LC MS rt: 1.93 min [M+H]⁺: 265.2 (met. a)

O2.011 1-(3-tert-Butyl-5-ethoxyphenyl)ethanone

Methyl 3-tert-butyl-5-hydroxybenzoate (O6.043) was reacted with ethyliodide analogously to O5.043 and converted to the title compoundanalogously to the sequence of O4.043 to O2.043. 390 mg were obtained.

LC-MS rt: 1.72 min [M+H]⁺: 221.3 (met. a)

O2.012 1-(3-tert-Butyl-5-propoxymethylphenyl)ethanone

Proceeding from methyl 3-tert-butyl-5-hydroxymethylbenzoate and propyliodide, the title compound (333 mg) was prepared analogously to O5.008to O2.008.

LC-MS rt: 1.81 min [M+H]⁺: 261.2 (met. a)

O2.013 1-(3-tert-Butyl-4,5-bis(cyclopropylmethoxy)phenyl)ethanone

Proceeding from 2-bromo-6-tert-butyl-4-(1,1-dimethoxyethyl)phenol andcyclopropyl bromide, the title compound (547 mg) was preparedanalogously to O4.010 to O2.010.

LC-MS rt: 2.10 min [M+H]⁺: 317.4 (met. a)

O2.014 1-(3-Methoxy-5-trifluoromethylphenyl)ethanone

3,N-Dimethoxy-N-methyl-5-trifluoromethylbenzamide (O3.014, 460 mg) wasinitially charged in THF (15 ml) under at RT Ar dissolved. Thereafter,the mixture was cooled to 0° C., and methylmagnesium bromide (1.5 ml; 3M in diethyl ether) was added dropwise. Subsequently, the ice bath wasremoved and the mixture was stirred at RT for 2 h. Then the mixture wasadmixed with 1 N hydrochloric acid while cooling with ice, diluted withwater and extracted three times with EA. The combined EA phases weredried over sodium sulfate, filtered and concentrated. 349 mg of thetitle compound were isolated.

¹H NMR (500 MHz, DMSO-d6) [ppm]: 7.80 (1H), 7.73 (1H), 7.53 (1H), 3.92(3H), 2.66 (3H)

O2.015 1-(3-tert-Butyl-5-methoxyphenyl)ethanone

Methyl 3-tert-butyl-5-hydroxybenzoate (O6.043) was reacted with methyliodide analogously to O5.043 and converted to the title compoundanalogously to the sequence of O4.043 to O2.043. 880 mg were obtained.

LC-MS rt: 1.65 min [M+H]⁺: 207.1 (met. a)

O2.016 1-(3-tert-Butyl-5-cyclopropylmethoxyphenyl)ethanone

Methyl 3-tert-butyl-5-hydroxybenzoate (O6.043) was reacted withcyclopropylmethyl bromide analogously to O5.043, and converted to thetitle compound analogously to the sequence O4.043 to O2.043. 1.02 g wereobtained.

LC-MS rt: 1.86 min [M+H]⁺: 247.1 (met. a)

O2.017 1-(3-tert-Butyl-5-cyclobutylmethoxyphenyl)ethanone

Methyl 3-tert-butyl-5-hydroxybenzoate (O6.043) was reacted withbromomethylcyclobutane analogously to O5.043 and converted to the titlecompound analogously to the sequence O4.043 to O2.043. 252 mg wereobtained.

LC-MS rt: 2.07 min [M+H]⁺: 261.2 (met. a)

O2.018 1-(3-Benzyloxymethyl-5-tert-butylphenyl)ethanone

Methyl 3-tert-butyl-5-hydroxymethylbenzoate was reacted with benzylbromide analogously to O5.043 and converted to the title compoundanalogously to the sequence O4.008 to O2.008. 638 mg were obtained.

LC-MS rt: 1.93 min [M+H]⁺: 297.2 (met. a)

O2.019 1-(3-Cyclohexylmethoxy-4,5-dimethoxyphenyl)ethanone

3-Cyclohexylmethoxy-4,5,N-trimethoxy-N-methylbenzamide (420 mg) wasconverted and worked up analogously to O2.059. No silica gelpurification was performed. 370 mg were obtained.

LC-MS rt: 1.82 min [M+H]⁺: 293.2 (met. a)

O2.020 1-(3-tert-Butyl-5-methoxymethylphenyl)ethanone

Methyl 3-tert-butyl-5-hydroxymethylbenzoate was reacted with methyliodide analogously to O5.043, and converted to the title compoundanalogously to the sequence O4.008 to O2.008. 1.54 g were obtained.

LC-MS rt: 1.58 min [M+H]⁺: 221.1 (met. a)

O2.021 1-(3-Chloro-5-methoxyphenyl)ethanone

3-Chloro-5-methoxybenzoic acid (3 g) was reacted analogously toO3.043/O2.043 with thionyl chloride (23.3 ml) andN,O-dimethylhydroxylamine hydrochloride (1.57 g) and methylmagnesiumbromide (8.91 ml). 2.42 g were obtained.

¹H NMR (500 MHz, DMSO-d6) [ppm]: 7.54 (1H), 7.40 (1H), 7.30 (1H), 3.84(3H), 2.58 (3H)

O2.030 1-(3-Isopropyl-5-methoxyphenyl)ethanone

Methyl 3-hydroxy-5-isopropylbenzoate was reacted with methyl iodideanalogously to O5.043 and converted to the title compound analogously tothe sequence O4.043 to O2.043. 425 mg were obtained. LC-MS rt: 1.54 min[M+H]⁺: 193.1 (met. a)

O2.031 1-(3-Cyclohexylmethoxy-5-ethoxyphenyl)ethanone

1-(3,5-Dihydroxyphenyl)ethanone (1.0 g) and ethyl bromide (0.531 ml)were dissolved at RT in DMF (20 ml), and sodium hydride (189 mg) wasadded. After stirring at 50° C. for 2 h, cyclohexylmethyl bromide (1.36ml) was added, followed by further sodium hydride (315 mg). Afterstirring at 50° C. for another 2 h, the DMF was drawn off and theresidue was taken up in EA, washed with water, dried, filtered andconcentrated. The residue was purified using silica gel (80 g cartridge,n-heptane/EA gradient of 0-20% within 60 min). 378 mg of the titlecompound were obtained. LC-MS rt: 2.07 min [M+H]⁺: 277.2 (met. a)

O2.032 1-(3-Bromo-5-methoxyphenyl)ethanone

Methyl 3-bromo-5-methoxybenzoate (O5.032; 2.50 g) was converted to thetitle compound analogously to the sequence of O4.043, 03.043 and O2.059.1.45 g were obtained.

LC-MS rt: 1.46 min [M+H]⁺: 229.0 (met. a)

O2.034 1-[3-(3,3-Dimethylbutoxy)-5-ethoxyphenyl]ethanone

1-(3,5-Dihydroxyphenyl)ethanone (3.0 g) were converted analogously toO2.031. Instead of cyclohexylbromide, however,1-bromo-3,3-dimethylbutane was used. After chromatography, 960 mg of thetitle compound were obtained.

LC-MS rt: 1.99 min [M+H]⁺: 265.2 (met. a)

O2.035 1-(3-Cyclohexylmethoxy-5-methoxyphenyl)ethanone

1-(3-Hydroxy-5-methoxyphenyl)ethanone (O3.033; 1.5 g) andbromomethylcyclohexane (1.76 g) were dissolved in DMF (20 ml), andsodium hydride (260 mg) was added. After stirring at 50° C. for 24 h,the DMF was drawn off. The residue was taken up in EA, washed withwater, dried, filtered and concentrated. The residue was purified usingsilica gel (40 g cartridge, n-heptane/EA 0-50% within 30 min). 1.33 g ofthe title compound were obtained.

LC-MS rt: 1.93 min [M+H]⁺: 263.2 (met. a)

O2.041 1-(5-Bromo-2,3-dimethoxyphenyl)ethanone

5-Bromo-2,3-dimethoxybenzoic acid (2 g) was converted to the benzamidederivative analogously to O3.043, and the latter to the title compoundanalogously to O2.059. 1.1 g of the title compound were obtained. LC-MSrt: 3.70 min [M+H]⁺: 259.0 (met. d)

O2.042 1-(3-Chloro-4,5-dimethoxyphenyl)ethanone

3-Chloro-4,5-dimethoxybenzoic acid (1 g) was converted to the benzamidederivative analogously to O3.043, and the latter to the title compoundanalogously to O2.059. 495 mg of the title compound were obtained. LC-MSrt: 1.55 min [M+H]⁺: 215.1 (met. a)

O2.043 1-[3-tert-Butyl-5-(2-methoxyethoxy)phenyl]ethanone

3-tert-Butyl-N-methoxy-5-(2-methoxyethoxy)-N-methylbenzamide (O3.043;1.35 g) was dissolved in THF (40 ml), methylmagnesium bromide (3.05 ml,3 M in ether) was added dropwise at 0° C. and then the mixture wasstirred at RT for 2 h. Then the mixture was admixed with 1 Nhydrochloric acid (50 ml), diluted with water and extracted by shakingthree times with EA. Then the combined EA phases were dried overmagnesium sulfate, filtered and concentrated. The residue was purifiedusing silica gel (40 g cartridge, n-heptane/EA gradient of 0-30% in 30min). 1.0 g of the title compound were obtained.

LC-MS rt: 1.58 min [M+H]⁺: 251.3 (met. a)

O2.044 1-[3-Morpholin-4-yl-5-(pentafluorosulfanyl)phenyl]ethanone

N-Methoxy-N-methyl-3-morpholin-4-yl-5-(pentafluorosulfanyl)benzamide(O3.044; 2.38 g) was converted and worked up analogously to O2.043. Thepurification was effected using silica gel (80 g cartridge, n-heptane/EAgradient of 0-70% within 40 min). 1.1 g of the title compound wereobtained.

LC-MS rt: 1.57 min [M+H]⁺: 332.0 (met. a)

O2.059 1-[3-tert-Butyl-5-(3-hydroxypropoxy)phenyl]ethanone

3-tert-Butyl-N-methoxy-N-methyl-5-[3-(tetrahydropyran-2-yloxy)propoxy]benzamide(O3.059; 5.49 g) was dissolved in THF (100 ml), cooled to 0° C. andadmixed with lithium bis(trimethylsilyl)amide (14.47 ml, 1 M in MTBether). After stirring at 0° C. for 30 min, methylmagnesium bromide(9.65 ml, 3 M in ether) was added dropwise. The cooling bath was removedand, after stirring at RT for 2 h, the mixture was diluted with waterand extracted by shaking with EA. The EA phase was dried over magnesiumsulfate, filtered and concentrated by rotary evaporation. The residuewas purified using silica gel (200 g, n-heptane/EA 4:1). 3.4 g of thetitle compound were obtained.

¹H NMR (500 MHz, DMSO-d6) [ppm] (representative signals): 7.53 (1H);7.28 (1H); 7.17 (1 H); 4.57 (1H, —O—C(—C)H—O—); 4.11 (2H); 2.57 (3H)

O2.0611-{3-tert-Butyl-5-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}ethanone

Proceeding from methyl 3-tert-butyl-5-hydroxybenzoate (O6.043) and2-(2-bromoethoxy)-tetrahydropyran, the synthesis sequence O5.059 toO2.059 was followed. 3.9 g of the title compound were obtained.

¹H NMR (500 MHz, DMSO-d6) [ppm] (representative signals): 7.53 (1H),7.31 (1H), 7.20 (1H), 4.66 (1H, —O—C(—C)H—O—), 4.20 (2H), 2.58 (3H)

O2.0701-{3-tert-Butyl-4-methoxy-5-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}ethanone

Analogously to O2.071,1-(3-tert-butyl-5-hydroxy-4-methoxyphenyl)ethanone (O3.070; 5.0 g) wasreacted with 2-(2-bromoethoxy)tetrahydropyran (5.64 g). However, thecrude product was purified using silica gel (40 g cartridge,n-heptane/EA gradient of 0-50% within 60 min). 6.68 g of the titlecompound were obtained.

¹H NMR (500 MHz, DMSO-d6) [ppm] (representative signals): 7.50 (2H,aromatic), 4.70 (1H, —O—C(—C)H—O—), 3.90 (3H, —OCH₃), 2.54 (3H, acetyl)

O2.0711-{3-tert-Butyl-4-methoxy-5-[3-(tetrahydropyran-2-yloxy)propoxy]phenyl}ethanone

1-(3-tert-Butyl-5-hydroxy-4-methoxyphenyl)ethanone (O3.070; 6.9 g) and2-(3-bromo-propoxy)tetrahydropyran (8.31 g) were dissolved in DMF (80ml), and sodium hydride (894 mg) was added. After stirring at RT for 5hours, the solvent was drawn off and the residue was taken up with EA.The EA phase was washed with water, dried and concentrated. 12.7 g ofthe title compound were obtained as a crude product in sufficientpurity.

¹H NMR (400 MHz, DMSO-d6) [ppm] (representative signals): 4.57 (1H,—O—C(—C)H—O—), 2.54 (3H, acetyl)

O2.075N-[3-Acetyl-5-(pentafluorosulfanyl)phenyl]-2,2,2-trifluoro-N-methylacetamide

In a microwave insert,N-(3-acetyl-5-pentafluorosulfanylphenyl)-2,2,2-trifluoroacetamide(O3.075; 0.25 g) was dissolved in absolute dimethoxyethane (7.5 ml),powdered potassium carbonate was added and the mixture was admixed withiodomethane (80 μl). Subsequently, the mixture was heated in themicrowave to 100° C. for 40 min. Once furtherN-(3-acetyl-5-pentafluorosulfanylphenyl)-2,2,2-trifluoroacetamide (4×250mg) had been converted in the manner described, the five batches wereworked up together, by decanting from potassium carbonate into 1 Nhydrochloric acid with ice cooling. After repeatedly washing thepotassium carbonate residue with dimethoxyethane, the aqueous phase wasextracted five times with ethyl acetate. The combined extracts weredried over magnesium sulfate, filtered and concentrated.

The residue was purified by means of preparative HPLC (met. A). Theproduct-containing fractions were combined, freed of the acetonitrileand extracted five times with ethyl acetate. The combined extracts weredried over magnesium sulfate, filtered and concentrated. 1.03 g of thedesired compound were obtained. LC-MS rt: 1.62 min [M+H]⁺: 372.0 (met.a)

O3 O3.0041-Bromo-5-(1,1-dimethoxyethyl)-2-methoxy-3-trifluoromethylbenzene

1-(3-Bromo-4-hydroxy-5-trifluoromethylphenyl)ethanone (O4.004; 6.8 g)was dissolved in methanol (50 ml) and admixed successively withDL-10-camphorsulfonic acid (111 mg) and trimethyl orthoformate (8 ml).After stirring at RT for 2 h, DMF (75 ml), potassium carbonate (4.98 g)and then slowly, while cooling with ice, iodomethane (3 ml) were added.After stirring at RT for 4 h, the reaction mixture was left to standovernight and then admixed with n-heptane/water, and the organic phasewas removed. The aqueous phase was extracted by shaking once more withn-heptane, and the combined organic phases were then dried overmagnesium sulfate, filtered and concentrated. 7 g of the title compoundwere obtained in sufficient purity.

¹H NMR (500 MHz, DMSO-d6) [ppm]: 7.90 (1H), 7.62 (1H), 3.89 (3H), 3.10(6H), 1.49 (3 H)

O3.007 3,N-Dimethoxy-N-methyl-5-(pentafluorosulfanyl)benzamide

Methyl 3-methoxy-5-(pentafluorosulfanyl)benzoate (O4.007; 2.5 g) wasdissolved in absolute THF (65 ml), and N,O-dimethylhydroxylaminehydrochloride (1.2 g) was added. Then the mixture was cooled to −15° C.and isopropylmagnesium bromide solution (13.59 ml, 2 M in THF) was addeddropwise. After 20 min, the cooling bath was removed and the mixture wasstirred at RT for 1 h. Then ammonium chloride solution was added and theaqueous phase was extracted three times with ethyl acetate. The combinedextracts were dried over magnesium sulfate, filtered and concentrated.The crude product thus obtained still contained significant reactant,and was therefore converted and worked up again as described above. Noreactant was present any longer in the residue which was then obtained.Purification was effected by means of preparative HPLC (met. A). Theproduct-containing fractions were combined and freed of theacetonitrile, and the aqueous phase was extracted three times with EA.The combined extracts were dried over magnesium sulfate, filtered andconcentrated. 1.78 g of the desired compound were obtained.

¹H NMR (400 MHz, CDCl₃) [ppm]: 7.70 (1H), 7.37 (1H), 7.24 (1H+CDCl₃),3.88 (3H), 3.56 (3H)

O3.008 3-tert-Butyl-5-ethoxymethyl-N-methoxy-N-methylbenzamide

Analogously to O3.043, 3-tert-butyl-5-ethoxymethylbenzoic acid (O4.008;1.15 g) was first converted to the acid chloride (1.24 g), and then the3-tert-butyl-5-ethoxymethyl-benzoyl chloride obtained was convertedfurther. 854 mg of the title compound were obtained.

LC-MS rt: 3.32 min [M+H]⁺: 280.2 (met. d)

O3.010 1-(3-tert-Butyl-4-ethoxy-5-hydroxyphenyl)ethanone

1-Bromo-3-tert-butyl-5-(1,1-dimethoxyethyl)-2-ethoxybenzene (O4.010;19.68 g) was converted analogously to O3.070. 5.15 g of the titlecompound were obtained.

LC-MS rt: 0.972 min [M+H]⁺: 237.1 (met. b)

O3.014 3,N-Dimethoxy-N-methyl-5-trifluoromethylbenzamide

Methyl 3-methoxy-5-trifluoromethylbenzoate (O4.014, 1 g) andN,O-dimethylhydroxylamine (416 mg) were initially charged in THF (30ml). Thereafter, the mixture was cooled to −15° C., andisopropylmagnesium chloride (3.2 ml; 2 M in THF) was added dropwisewithin 10 min. The mixture was stirred at −15° C. for another 20 minbefore the cooling bath was removed. After 3 h, the mixture was cooledagain to −15° C. and further isopropylmagnesium chloride (3.2 ml) wasadded. After the cooling bath had been removed, the mixture was stirredat RT for another hour, then admixed with 20% ammonium chloride solutionand extracted three times with EA. The combined EA phases were driedover sodium sulfate, filtered and concentrated. The residue was purifiedusing silica gel (50 g cartridge, DCM as eluent). 465 mg of the titlecompound were obtained, as well as 427 mg of reactant.

LC-MS rt: 1.36 min [M+H]⁺: 264.0 (met. a)

O3.033 1-(3-Hydroxy-5-methoxyphenyl)ethanone

1-(3,5-Dihydroxyphenyl)ethanone (3 g) and methyl iodide (2.80 g) weredissolved in DMF (40 ml), and sodium hydride (568 mg) was added. Afterstirring at RT for 2 h, the DMF was drawn off. The residue was taken upin EA and washed with water, dried, filtered and concentrated. Theresidue was purified using silica gel (89 g cartridge, n-heptane/EA0-50% within 30 min). 1.12 g of the title compound were obtained.

¹H NMR (500 MHz, DMSO-d6) [ppm]: 9.8 (1H); 6.93 (2H); 6.58 (1H); 3.76(3H); 2.50 (3H+DMSO)

O3.043 3-tert-Butyl-N-methoxy-5-(2-methoxyethoxy)-N-methylbenzamide

3-tert-Butyl-5-(2-methoxyethoxy)benzoic acid (O4.043; 1.9 g) wasdissolved in thionyl chloride (10.9 ml), kept under reflux for 2 h andthen concentrated. The resulting 3-tert-butyl-5-(2-methoxyethoxy)benzoylchloride (2.04 g) was dissolved in DCM (20 ml) and admixed withdimethylhydroxylamine (734 mg), then Hünig's base (1.37 ml) was addedand the mixture was stirred at RT for 1 h. Then the mixture was dried,the residue was taken up in EA, and the mixture was washed four timeswith water, dried over magnesium sulfate, filtered and concentrated byrotary evaporation. The residue was purified using silica gel (40 gcartridge, n-heptane/EA gradient of 0-50% in 40 min). 1.36 g of thetitle compound were obtained.

LC-MS rt: 1.43 min [M+H]⁺: 296.3 (met. a)

O3.044

N-Methoxy-N-methyl-3-morpholin-4-yl-5-(pentafluorosulfanyl)benzamide

3-Amino-N-methoxy-N-methyl-5-(pentafluorosulfanyl)benzamide (O5.075; 6.3g) was dissolved in DMF (80 ml), and cesium carbonate (10.1 g), sodiumiodide (0.62 g) and bis(2-bromoethyl)ether (19.37 g) were added. Themixture was divided between 10 microwave vessels, each of which washeated to 130° C. for 3 h. Subsequently, the batches were combined andfreed of solvent. The residue was taken up in EA and washed with water.The EA phase was dried and concentrated. The residue was purified usingsilica gel (120 g cartridge, n-heptane/EA gradient of 0-100% within 30min). 2.48 g of the title compound were obtained.

LC-MS rt: 1.41 min [M+H]⁺: 377.0 (met. a)

O3.0593-tert-Butyl-N-methoxy-N-methyl-5-[3-(tetrahydropyran-2-yloxy)propoxy]benzamide

3-tert-Butyl-5-[3-(tetrahydropyran-2-yloxy)propoxy]benzoic acid (O4.059;4.90 g) and N,O-dimethylhydroxylaminehydrochloride (1.42 g) weredissolved in DMF (80 ml) and admixed with Hünig's base (4.81 ml) andTOTU (4.78 g). After stirring for 2 h, the mixture was left to standovernight. Then the DMF was drawn off, the mixture was partitionedbetween EA and saturated sodium hydrogencarbonate solution, and the EAphase was removed, dried over magnesium sulfate, filtered andconcentrated. 5.49 g of the title compound were obtained.

¹H NMR (500 MHz, DMSO-d6) [ppm] (representative signals): 7.12 (1H),7.01 (1H), 6.90 (1H), 4.56 (1H, —O—C(—C)H—O—), 4.06 (2H), 3.57 (3H),3.22 (3H)

O3.070 1-(3-tert-Butyl-5-hydroxy-4-methoxyphenyl)ethanone

1-Bromo-3-tert-butyl-5-(1,1-dimethoxyethyl)-2-methoxybenzene (O4.070;36.3 g) was dissolved in THF (1 l), n-butyllithium (52.6 ml; 2.5 M inhexane) was added dropwise at −75° C. under argon, and the mixture wasstirred for a further 30 min. Then trimethyl borate (37.3 ml) was addeddropwise and the mixture was allowed to come to RT within 2 h.Subsequently, sodium hydroxide (4.4 g, dissolved in 10 ml of water) andhydrogen peroxide solution (62.3 ml; 35% in water) were addedsuccessively. After stirring at RT for 2 h, the mixture was left tostand overnight. Then water and EA were added and the mixture wasacidified with hydrochloric acid. After removing the EA phase, this wasdried over magnesium sulfate and concentrated. The residue was purifiedusing silica gel (330 g cartridge, n-heptane/EA gradient of 0-50% within60 min). 14 g of the title compound were obtained.

LC-MS rt: 0.90 min [M+H]⁺: 223.1 (met. b)

O3.075 N-(3-Acetyl-5-pentafluorosulfanylphenyl)-2,2,2-trifluoroacetamide

N-Methoxy-N-methyl-3-(pentafluorosulfanyl)-5-(2,2,2-trifluoroacetylamino)benzamide(O4.075; 1.65 g) was dissolved in THF (25 ml). At 0° C., lithiumbis(trimethylsilyl)amide (0.9 ml) was added while stirring. After 30min, methylmagnesium bromide (3.5 ml, 3 M in diethyl ether) was addeddropwise. After the addition had ended, the ice bath was removed and themixture was stirred at RT for 2 h. While cooling, 1 N hydrochloric acid,water and EA were then added. After removing the organic phase, theaqueous phase was extracted twice more with EA. The combined EA phaseswere dried with magnesium sulfate, filtered and concentrated. The crudeproduct is a mixture ofN-(3-acetyl-5-pentafluorosulfanyl-phenyl)-2,2,2-trifluoroacetamide and1-[3-amino-5-(pentafluorosulfanyl)phenyl]ethanone, and so the crudeproduct (1.3 g) was taken up in methylene chloride (60 ml) and admixedwith triethylamine (155 μl). Thereafter, trifluoroacetic anhydride (160μl) was added while stirring. After stirring at RT for 3 h, water andsaturated sodium hydrogencarbonate solution were added, the phases wereseparated and the DCM phase was washed three times more with water. TheDCM phase was dried with magnesium sulfate, filtered and concentrated.1.3 g of the title compound were obtained.

LC-MS rt: 1.61 min [M+H]⁺: 358.0 (met. a)

O4 O4.004 1-(3-Bromo-4-hydroxy-5-trifluoromethylphenyl)ethanone

1-(4-Hydroxy-3-trifluoromethylphenyl)ethanone (5 g) was initiallycharged in acetonitrile (150 ml) at RT while stirring, and cooled to−10° C. At this temperature, N-bromosuccinimide (4.5 g, dissolved in 100ml of acetonitrile) was added dropwise. Then the cooling bath wasremoved and the mixture was stirred for a further 5 h. After standingovernight, ¾ of the solvent was drawn off and the residue was admixedwith n-heptane/water. The organic phase was removed and washed once with5% sodium thiosulfate solution and once with water. The precipitateformed was filtered off with suction, washed and dried. 6.9 g of thetitle compound were obtained in sufficient purity. LC-MS rt: 1.35 min[M+H]⁺: 283.0 (met. a)

O4.007 Methyl 3-methoxy-5-(pentafluorosulfanyl)benzoate

3-Hydroxy-5-(pentafluorosulfanyl)benzoic acid (O5.007; 3.0 g) wasdissolved in absolute DMF (75 ml). Then iodomethane (3.6 ml) was addedwhile stirring, followed by finely powdered potassium carbonate (6.3 g).After stirring at 40° C. for 5 hours, the mixture was cooled and admixedwith water (250 ml). The mixture was then extracted four times withether (100 ml). The combined extracts were each washed once with 1 Nsodium hydroxide solution (75 ml) and water (100 ml), dried overmagnesium sulfate, filtered and concentrated. 2.9 g of the desiredcompound were obtained.

¹H NMR (400 MHz, CDCl₃) [ppm]: 8.00 (1H), 7.70 (1H), 7.47 (1H), 3.96(3H), 3.90 (3H)

O4.008 3-tert-Butyl-5-ethoxymethylbenzoic acid

Methyl 3-tert-butyl-5-ethoxymethylbenzoate (O5.008; 1.18 g) wasconverted analogously to O4.043. However, the crude product obtained wassubsequently purified using silica gel (50 g cartridge, n-heptane/EAgradient of 0-50% within 30 min). 1.15 g of the title compound wereobtained.

¹H NMR (400 MHz, DMSO-d₆) [ppm]: 12.90 (1H), 7.86 (1H), 7.73 (1H), 7.57(1H), 4.50 (2H), 3.50 (1H), 1.30 (9H), 1.16 (3H)

O4.010 1-Bromo-3-tert-butyl-5-(1,1-dimethoxyethyl)-2-ethoxybenzene

2-Bromo-6-tert-butyl-4-(1,1-dimethoxyethyl)phenol (20 g; for synthesissee CA02515715) was alkylated with ethyl iodide analogously to theconditions of O4.070. 19.67 g of the title compound were obtained.

¹H NMR (500 MHz, DMSO-d6) [ppm]: 7.46 (1H), 7.33 (1H), 4.03 (2H), 3.06(6H), 1.43 (3H), 1.38 (3H), 1.35 (9H)

O4.014 Methyl 3-methoxy-5-trifluoromethylbenzoate

3-Hydroxy-5-trifluoromethylbenzoic acid (2 g) was initially charged atRT in DMF (15 ml) while stirring, and admixed dropwise with methyliodide (3.0 ml). After adding potassium carbonate (5.6 g), the mixturewas stirred for 5 h and left to stand overnight. It was then admixedwith water and extracted three times with MtB ether. The combined MTBether phases were dried over sodium sulfate, filtered and concentrated.2.29 g of the title compound were obtained.

¹H NMR (500 MHz, DMSO-d6) [ppm]: 7.76 (1H), 7.70 (1H), 7.55 (1H), 3.91(3H), 3.89 (3 H)

O4.043 3-tert-Butyl-5-(2-methoxyethoxy)benzoic acid

Methyl 3-tert-butyl-5-(2-methoxyethoxy)benzoate (O5.043; 2.0 g) wasdissolved in methanol (30 ml) and THF (60 ml), and lithium hydroxidesolution (30 ml, 1 M in water) was added. The mixture was heated to 40°C. and stirred for 3 h. Then the organic solvents were drawn off and theaqueous phase was adjusted to pH 3 with 1 N hydrochloric acid. Themixture was extracted with EA, dried, filtered and concentrated. 1.9 gof the title compound were obtained.

LC-MS rt: 1.40 min [M+H-H₂O]⁺: 235.3 (met. a)

O4.059 3-tert-Butyl-5-[3-(tetrahydropyran-2-yloxy)propoxy]benzoic acid

Methyl 3-tert-butyl-5-[3-(tetrahydropyran-2-yloxy)propoxy]benzoate(O5.059; 5.37 g) was dissolved in methanol (80 ml) and THF (160 ml), andlithiumhydroxide solution (61.28 ml, 1 M in water) was added. Afterstirring at 40° C. for 2 h, the mixture was dried, and the residue wastaken up with water and freeze-dried. The product obtained was stirredwith DCM, filtered and dried. 4.9 g of product were obtained.

¹H NMR (500 MHz, DMSO-d6) [ppm] (representative signals): 7.52 (1H),7.26 (1H), 6.80 (1H), 4.57 (1H, —O—C(—C)H—O—), 4.02 (2H)

O4.070 1-Bromo-3-tert-butyl-5-(1,1-dimethoxyethyl)-2-methoxybenzene

1-Bromo-3-tert-butyl-5-(1,1-dimethoxyethyl)-2-methoxybenzene wassynthesized analogously to patent application CA 02515715.

¹H NMR (500 MHz, DMSO-d6) [ppm]: 7.47 (1H), 7.33 (1H), 3.85 (3H), 3.07(6H), 1.43 (3H), 1.35 (9H)

O4.075N-Methoxy-N-methyl-3-(pentafluorosulfanyl)-5-(2,2,2-trifluoroacetylamino)benzamide

3-Amino-N-methoxy-N-methyl-5-pentafluorosulfanylbenzamide (O5.075; 1.45g) was dissolved in methylene chloride (15 ml), and, while stirring,triethylamine (0.8 ml) followed by trifluoroacetic anhydride (0.85 ml)were added with exclusion of moisture. After stirring at RT for 3 h andstanding overnight, water and saturated sodium hydrogencarbonatesolution were added, the phases were separated and the methylenechloride phase was washed three times more with water, dried overmagnesium sulfate, filtered and concentrated. The product obtained (1.75g) was used in the next stage without further purification.

LC-MS rt: 1.53 min [M+H]⁺: 403.0 (met. a)

O5 O5.007 3-Hydroxy-5-(pentafluorosulfanyl)benzoic acid

3-Amino-5-pentafluorosulfanylbenzoic acid (O6.007; 3.9 g) was dissolvedin 35% sulfuric acid (120 ml) and cooled to −5° C., and a solution ofsodium nitrite (1.1 g) in water (100 ml) was added dropwise within 10min. After 40 min, further nitrite solution was added (2 ml), andanother 2 ml and 1 ml after a further 20 min in each case. Then thecooling bath was removed and the mixture was heated to 100° C. After 5h, the mixture was cooled and the solution was decanted. The clear,acidic solution was extracted five times with ethyl acetate. Thecombined extracts were dried over magnesium sulfate, filtered andconcentrated. The crude product was recrystallized from ethylacetate/heptane. 3.6 g of the desired compound were obtained.

¹H NMR (400 MHz, DMSO-d₆) [ppm]: 10.72 (1H); 7.71 (1H); 7.57 (1H); 7.46(1H);

O5.008 Methyl 3-tert-butyl-5-ethoxymethylbenzoate

Methyl 3-tert-butyl-5-hydroxymethylbenzoate (2.0 g) was alkylated withethyl iodide analogously to the conditions of O5.043. 1.18 g of thetitle compound were obtained.

LC-MS rt: 3.81 min [M+H]⁺: 250.2 (met. d)

O5.032 Methyl 3-Bromo-5-methoxybenzoate

Methyl 3-bromo-5-hydroxybenzoate (O6.032; 2.52 g) was alkylated withmethyl iodide and worked up analogously to the conditions of O5.043. 2.5g of the title compound were obtained.

LC-MS rt: 1.58 min [M+H]⁺: 245.0 (met. a)

O5.043 Methyl 3-tert-butyl-5-(2-methoxyethoxy)benzoate

Methyl 3-tert-butyl-5-hydroxybenzoate (O6.043; 2.18 g) and1-bromo-2-methoxyethane (1.18 ml) were dissolved in DMF (30 ml) andsodium hydride (301 mg) was added while stirring. After stirring at RTfor 2 h, the solvent was drawn off. The residue was taken up in EA, andthe mixture was washed with water, dried and concentrated. The residuewas purified using silica gel (80 g cartridge, n-heptane/MtB ethergradient of 0-30% in 60 min). 2.0 g of the title compound were obtained.

LC-MS rt: 1.69 min [M+H-HOCH₃]⁺: 235.2 (met. a)

O5.059 Methyl3-tert-butyl-5-[3-(tetrahydropyran-2-yloxy)propoxy]benzoate

Methyl 3-tert-butyl-5-hydroxybenzoate (O6.043; 3.22 g) and2-(3-bromopropoxy)-tetrahydropyran (4.14 g) were dissolved in DMF (30ml), and sodium hydride (445 mg) was added. After stirring at RT for 3h, the mixture was left to stand overnight. Then the DMF was drawn offand the residue was taken up in EA, washed with water, dried, filteredand concentrated. 5.37 g of product were obtained.

¹H NMR (500 MHz, DMSO-d6) [ppm] (representative signals): 7.56 (1H),7.28 (1H), 7.19 (1H), 4.57 (1H, —O—C(—C)H—O—), 4.10 (2H)

O5.075 3-Amino-N-methoxy-N-methyl-5-pentafluorosulfanylbenzamide

N-Methoxy-N-methyl-5-nitro-3-pentafluorosulfanylbenzamide (O6.075; 4.2g) was dissolved in methanol (120 ml), and Raney nickel (about 700 mg)was added. With a hydrogen balloon attached, hydrogenation was effectedon a magnetic stirrer. After 5 h, the catalyst was filtered off andwashed with methanol. The filtrate was concentrated under reducedpressure and the residue was purified by means of preparativechromatography. The product-containing fractions were combined, freed ofthe acetonitrile, basified with sodium hydrogencarbonate solution andextracted three times with ethyl acetate. The combined extracts weredried over magnesium sulfate, filtered and concentrated. 1.73 g of thedesired compound were obtained.

LC-MS rt: 1.27 min [M+H]⁺: 307.0 (met. a)

O6 O6.007 3-Amino-5-pentafluorosulfanylbenzoic acid

3-Pentafluorosulfanylbenzoic acid (15 g) was dissolved in fuming nitricacid (120 ml) and stirred at RT with exclusion of moisture. Thenconcentrated sulfuric acid (7.5 ml) was added and the mixture wasstirred at 75° C. After stirring at 75° C. for 8 h, the mixture was leftto stand overnight, then further sulfuric acid (1.5 ml) was added andthe mixture was heated to 75° C. while stirring for 8 h. After beingleft to stand overnight, the mixture was added to ice-water and stirredfor 2 h. Then the precipitate was filtered off with suction and driedunder high vacuum. 13.7 g of 3-pentafluorosulfanyl-5-nitrobenzoic acidwere obtained.

Subsequently, the 3-pentafluorosulfanyl-5-nitrobenzoic acid (5 g) wasdissolved in methanol (300 ml), Raney nickel (about 750 mg) was addedand hydrogenation was effected under a hydrogen atmosphere (hydrogenballoon). After 3 h, the catalyst was filtered off and the filterresidue was washed thoroughly with methanol. The filtrate wasconcentrated and dried. The residue was purified using silica gel (2×50g cartridge, n-heptane/EA gradient of 0-100% within 60 min). 3.9 g ofthe title compound were obtained.

¹H NMR (400 MHz, DMSO-d₆) [ppm]: 13.30 (1H); 7.37 (2H); 7.23 (1H); 5.98(2H)

O6.043 Methyl 3-tert-butyl-5-hydroxybenzoate

3-tert-Butyl-5-hydroxybenzoic acid (O7.043; 1.93 g) was dissolved inmethanol (20 ml), and thionyl chloride (0.937 ml) was slowly addeddropwise while stirring. After stirring at 65° C. for 1 h, the mixturewas dried, the residue was taken up in DCM, and the solution was washedwith saturated sodium hydrogencarbonate solution, dried over MgSO₄,filtered and concentrated by rotary evaporation. 2.19 g of the titlecompound were obtained.

LC-MS rt: 1.44 min [M+H]⁺: 209.2 (met. a)

O6.075 N-Methoxy-N-methyl-5-nitro-3-pentafluorosulfanylbenzamide

3-Pentafluorosulfanylbenzoic acid (5.0 g) was dissolved in fuming nitricacid (20 ml) and stirred at RT with exclusion of moisture. Thenconcentrated sulfuric acid (3 ml) was added and the mixture was stirredat 75° C. After stirring at 75° C. for 5 h, further sulfuric acid (2 ml)was added and the mixture was stirred at 75° C. for a further 2 h. Afterbeing left to stand overnight, the mixture was poured onto ice-water andstirred for 2 h. Then the precipitate was filtered off with suction anddried under high vacuum. 4.2 g of 3-pentafluorosulfanyl-5-nitrobenzoicacid were obtained. A further 900 mg were obtained from the motherliquor after extracting three times with methylene chloride, drying thecombined methylene chloride phases over magnesium sulfate andconcentrating the solvent. Subsequently, 4.0 g of the3-pentafluorosulfanyl-5-nitrobenzoic acid were dissolved in thionylchloride (25 ml) while stirring and kept under reflux with exclusion ofmoisture for 10 h. After standing overnight at RT, excess thionylchloride was removed under reduced pressure, and the residue obtainedwas dissolved in dichloromethane (50 ml) and admixed while stirring withN,O -dimethylhydroxylaminex HCl (1.25 g) and diethylisopropylamine (1.66g). After stirring at RT for 1 h, the mixture was concentrated underreduced pressure, and the residue was dissolved in ethyl acetate andwashed five times with water. The organic phase was dried over magnesiumsulfate, filtered and concentrated. The 4.2 g of crude product obtainedwere used directly in the next stage. LC-MS rt: 1.50 min [M+H]⁺: 337.0(met. a)

O7 O7.043 3-tert-Butyl-5-hydroxybenzoic acid

3-Bromo-5-tert-butylbenzoic acid (5 g) was dissolved in THF (180 ml),and n-butyllithium (18.7 ml, 2.5 M in hexane) was added dropwise underargon and at −75° C., and stirred for a further 30 min. Then trimethylborate (6.63 ml) was added dropwise and the mixture was allowed to cometo RT within 1 h. Thereafter, sodium hydroxide (0.778 g), dissolved in 2ml of water, and hydrogen peroxide (12.89 ml, 30%) were added insuccession. After stirring at RT for 3 h, the mixture was left to standover the weekend. Then water and EA were added, the mixture was adjustedto pH 3 with 1 N hydrochloric acid and the EA phase was removed. Thisphase was washed three times with water, dried, filtered andconcentrated. The residue was purified using silica gel (120 gcartridge, n-heptane/MtB ether gradient of 0-50% in 60 min). 1.94 g ofthe title compound were obtained.

LC-MS rt: 1.18 min [M+H]⁺: 195.1 (met. a)

Example 11-{2-[3-Acetylamino-5-(pentafluorosulfanyl)phenyl]-2-oxoethyl}-3-amino-6-ethoxy-[1,2,4]triazolo[4,3-b]pyridazin-1-iumtrifluoroacetate

a) 3-Nitro-5-pentafluorosulfanylbenzoic acid

3-Pentafluorosulfanylbenzoic acid (5.0 g) was dissolved in fuming nitricacid (20 ml) and stirred at RT with exclusion of moisture. Thenconcentrated sulfuric acid (3 ml) was added and the mixture was stirredat 75° C. After stirring at 75° C. for 5 h, further sulfuric acid (1.5ml) was added and, after stirring at 75° C. for 2 h, left to standovernight. Then the mixture was added to ice-water and stirred for 2 h.The precipitate formed was filtered off with suction and dried underhigh vacuum. 4.2 g of 3-pentafluorosulfanyl-5-nitrobenzoic acid wereobtained. A further 900 mg were obtained from the mother liquor afterextracting three times with methylene chloride, drying the combinedmethylene chloride phases over magnesium sulfate and concentrating thesolvent. The precipitate was used in the next stage without furtherpurification.

¹H NMR (400 MHz, DMSO-d₆) [ppm]: 8.82 (1H); 8.80 (1H); 8.62 (1H)

b) N-Methoxy-N-methyl-5-nitro-3-pentafluorosulfanylbenzamide

3-Nitro-5-pentafluorosulfanylbenzoic acid (4.0 g) was dissolved inthionyl chloride (25 ml) while stirring and kept under reflux withexclusion of moisture for 10 h. After standing overnight, excess thionylchloride was removed under reduced pressure at RT, and the resultingresidue was dissolved in dichloromethane (50 ml) and admixed with N,O-dimethylhydroxylamine hydrochloride (1.25 g) and diethylisopropylamine(1.66 g) while stirring. After stirring at RT for 1 h, the mixture wasconcentrated under reduced pressure, and the residue was dissolved inethyl acetate and washed 5 times with water. The organic phase was driedover magnesium sulfate, filtered and concentrated. The resulting crudeproduct (4.2 g) was used directly in the next stage.

LC-MS rt: 1.50 min [M+H]⁺: 337.0

c) 3-Amino-N-methoxy-N-methyl-5-pentafluorosulfanylbenzamide

N-Methoxy-N-methyl-5-nitro-3-pentafluorosulfanylbenzamide (4.2 g) wasdissolved in methanol (120 ml), and Raney nickel (approx. 700 mg) wasadded. With a hydrogen balloon attached, hydrogenation was effected on amagnetic stirrer. After 5 h, the catalyst was filtered off and washedwith methanol. The filtrate was concentrated under reduced pressure andthe residue was purified by means of preparative HPLC. Theproduct-containing fractions were combined, freed of the acetonitrile,basified with sodium hydrogencarbonate solution and extracted threetimes with ethyl acetate. The combined extracts were dried overmagnesium sulfate, filtered and concentrated. 1.73 g of the desiredcompound were obtained.

LC-MS rt: 1.27 min [M+H]⁺: 307.0

d) 3-Acetylamino-N-methoxy-N-methyl-5-(pentafluorosulfanyl)benzamide

3-Amino-N-methoxy-N-methyl-5-pentafluorosulfanylbenzamide (1.2 g) wasdissolved in methylene chloride (15 ml), and triethylamine (0.7 ml)followed by acetic anhydride (1.75 ml) were added while stirring withexclusion of moisture. After stirring at RT for 3 h, water and saturatedsodium hydrogencarbonate solution were added, the phases were separatedand the methylene chloride phase was washed three times more with water,dried over magnesium sulfate, filtered and concentrated. The resultingproduct (1.3 g) was used in the next stage without further purification.

LC-MS rt: 1.26 min [M+H]⁺: 349.0

e) N-[3-Acetyl-5-(pentafluorosulfanyl)phenyl]acetamide

3-Acetylamino-N-methoxy-N-methyl-5-(pentafluorosulfanyl)benzamide (1.2g) was dissolved in absolute THF (30 ml) and stirred at 0° C. withlithium hexamethyldisilazide (721 μl; density: 0.8 g/1; 23% intent-butyl methyl ether) for 30 min. At 0° C., methylmagnesium bromide(2.87 ml, 3 M in diethyl ether) was then added dropwise while stirring.After stirring at RT for 2.5 h, further methylmagnesium bromide (1 ml, 3M in diethyl ether) was added and the mixture was stirred again for 2.5h. For workup, 1 N hydrochloric acid was added dropwise while coolingwith ice, followed by water and ethyl acetate. The organic phase wasremoved and the water phase was extracted twice more with ethyl acetate.The combined ethyl acetate phases were dried over sodium sulfate,filtered and concentrated. The crude product (1.03 g) was combined witha crude product prepared in the same way (75 mg) and purified usingsilica gel with dichloromethane-methanol as the eluent. 860 mg of thedesired compound were obtained. LC-MS rt: 1.34 min [M+H]⁺: 304.0

f) N-[3-(2-Bromoacetyl)-5-(pentafluorosulfanyl)phenyl]acetamide

N-[3-Acetyl-5-(pentafluorosulfanyl)phenyl]acetamide (859 mg) wasdissolved in a mixture of methanol (10 ml) and THF (10 ml) andphenyltrimethylammonium tribromide (1.065 g) was added in portions whilestirring. After stirring at RT for 2 h, the mixture was heated to 40° C.for a further 3 h. After cooling, the reaction mixture was added to 2 Nsulfuric acid and the aqueous phase was extracted 3 times with ethylacetate. The combined extracts were dried over sodium sulfate, filteredand concentrated. The crude product was purified using silica gel withethyl acetate/heptane as the eluent. 480 mg of the desired compound wereobtained.

LC-MS rt: 1.47 min [M+H]⁺: 382.0

g) 6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine as thehydrobromide and 6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine

(6-Chloropyridazin-3-yl)hydrazine (1 g) was dissolved in a mixture ofethanol (22.5 ml) and water (9 ml) at RT while stirring. Thereafter,cyanogen bromide (2.8 ml, 5 M in acetonitrile) was added dropwise whilestirring. After stirring for 6 h and leaving to stand overnight, theprecipitate was filtered off with suction and dried. In this way, 1.14 gof the desired product were obtained.

LC-MS rt: 0.24 min [M+H]⁺: 170.1

Further product was obtained in the form of the free base, by basifyingthe mother liquor with saturated potassium carbonate solution. Theprecipitate formed was filtered off with suction and dried (326 mg).

LC-MS rt: 0.24 min [M+H]⁺: 170.1

h) 6-Ethoxy-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine

6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (1.1 g) was taken upin a large amount of water and alkalized with saturated potassiumcarbonate solution. The solid which precipitated out was filtered offwith suction and dried (388 mg). Repeated extraction of the motherliquor with dichloromethane, drying of the combined organic phases oversodium sulfate, filtration and concentration afforded a further 228 mgof product in total. The resulting free base (616 mg) was dissolved inabsolute ethanol (40 ml) and admixed with solid sodium ethoxide (990 mg)in portions. After stirring at 55° C. for 2 h, water was added and theaqueous phase was extracted three times with dichloromethane. Thecombined extracts were dried over sodium sulfate, filtered andconcentrated. 709 mg of the desired compound were obtained.

LC-MS rt: 0.51 min [M+H]⁺: 180.1

i)1-{2-[3-Acetylamino-5-(pentafluorosulfanyl)phenyl]-2-oxoethyl}-3-amino-6-ethoxy-[1,2,4]triazolo[4,3-b]pyridazin-1-iumtrifluoroacetate

6-Ethoxy-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (40 mg) was initiallycharged in absolute DMF (3.5 ml) while stirring, andN-[3-(2-bromoacetyl)-5-(pentafluorosulfanyl)-phenyl]acetamide, dissolvedin absolute DMF (1.5 ml), was added dropwise. After stirring at RT for 5h and leaving to stand overnight, the solvent was drawn off and theresidue was purified by means of preparative HPLC, the 1-substitutedcompound sought eluting before the 2-substituted compound. The clean,product-containing fractions were combined, freed of the acetonitrileand freeze-dried. 13 mg of the desired compound were obtained. Thefractions contaminated with the 2-substituted isomer were likewisecombined, freed of the acetonitrile and freeze-dried. The residue wasthen purified using silica gel with a dichloromethane/methanol gradient,the 1-substituted compound sought eluting after the 2-substitutedcompound. The clean, product-containing fractions were combined anddried. The residue was taken up with acetonitrile and water, andfreeze-dried. A further 20 mg of the desired compound were obtained.

LC-MS rt: 1.10 min [M+H]⁺: 481.0

Example 43-Amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-trifluoromethyl-[1,2,4]triazolo[4,3-a]pyridin-1-iumtrifluoroacetate

6-Trifluoromethyl-[1,2,4]triazolo [4,3-a]pyridin-3-ylamine hydrobromide(W1.301; 309 mg) was dissolved in a little water, alkalized withsaturated potassium carbonate solution and extracted three times withEA. The combined EA phases were dried over magnesium sulfate, filteredand concentrated. 212 mg of the free base were obtained, which weredissolved in DMF (5 ml) while stirring at RT. Within 15 min,2-bromo-1-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)ethanone(O1.003; 427 mg dissolved in 1 ml of DMF) was added slowly. The mixturewas stirred at RT for 7 h and then left to stand overnight.Subsequently, it was stirred at 40° C. for 2 h and at 60° C. for 3 h.Then the solvent was drawn off and the residue was purified by means ofpreparative HPLC. The fractions comprising the desired product werecombined, freed of the ACN and freeze-dried. 90 mg of the title compoundwere obtained.

LC-MS rt: 1.34 min [M+H]⁺: 492.1

Further examples are detailed in the table below. They were carried outby couplings, carried out analogously to example 11) or example 4, oftriazolopyridazinenes or -pyridines of the “W1.” or “W2.” type with theappropriate acetophenone derivatives of the “O1.” type. The 2-alkylationproduct, which occurs with the same mass in the mass spectrum and isobtained as an impurity was removed by means of preparative HPLC, inwhich the desired 1-alkylation product normally eluted first under theconditions selected, while the 2-alkylation product eluted thereafter.Should a further separation using silica gel have been necessary (seeexample 10, the sequence of elution was reversed using the DCM/methanoleluent mixture. The 2-alkylation product eluted first, the 1-alkylationproduct second.

LC-MS rt [M]⁺ or Example Structure Name [min] [M + H]⁺ Ex.: 002

3-Amino-1-[2-(3,5-di-tert-butyl-4- hydroxyphenyl)-2-oxoethyl]-6-trifluoromethyl- [1,2,4]triazolo[4,3-a]pyridin-1-ium trifluoroacetate1.38 449.1 (met. a) Ex.: 003

3-Amino-1-[2-(3,5-di-tert-butyl-4- hydroxyphenyl)-2-oxoethyl]-[1,2,4]triazolo[4,3-a]pyridin-1-ium trifluoroacetate 1.23 381.2 (met. a)Ex.: 004

3-Amino-1-[2-(3-tert-butyl-4- methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6- trifluoromethyl-[1,2,4)triazolo[4,3-a]pyridin-1-ium trifluoroacetate 1.34 492.1 (met. a)Ex.: 005

3-Amino-1-[2-(3-tert-butyl-4- methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-5-methyl-7- trifluoromethyl-[1,2,4]triazolo[4,3-a]pyridin-1-ium trifluoroacetate 1.38 506.2 (met. a)Ex.: 006

3-Amino-5-chloro-1-{2-[3- methylamino-5- (pentafluorosulfanyl)phenyl]-2-oxoethyl}-[1,2,4]triazolo[4,3- a]pyridin-1-ium trifluoroacetate 1.14442.0 (met. a) Ex.: 007

3-Amino-7-ethoxy-6- ethoxycarbonyl-1-{2-[3- methylamino-5-(pentafluorosulfanyl)phenyl]-2- oxoethyl}-[1,2,4]triazolo[4,3-a]pyridin-1-ium trifluoroacetate 1.30 524.2 (met. a) Ex.: 008

3-Amino-1-[2-(3-tert-butyl-4- methoxy-5-morpholin-4-yl-phenyl)-2-oxoethyl]-7-ethoxy-6- ethoxycarbonyl-[1,2,4]triazolo[4,3-a]pyridin-1-ium trifluoroacetate 1.36 540.3 (met. a)Ex.: 009

3-Amino-1-[2-(3-tert-butyl-4- methoxy-5-morpholin-4-yl-phenyl)-2-oxoethyl]-7-ethoxy-6- methylcarbamoyl-[1,2,4]triazolo[4,3-a]pyridin-1-ium trifluoroacetate 1.28 525.3 (met. a)Ex.: 010

3-Amino-6-chloro-1-[2-(3,5-di- tert-butyl-4-hydroxyphenyl)-2-oxoethyl]-[1,2,4]triazolo[4,3-b] pyridazin-1-ium trifluoroacetate 1.26416.1 (met. a) Ex.: 011

3-Amino-1-[2-(3-tert-butyl-4- methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-ethoxy- [1,2,4]triazolo[4,3-b]pyridazin-1- iumchloride 1.32 469.2 (met. a) Ex.: 012

3-Amino-1-[2-(3-tert-butyl-4- methoxy-5-morpholin-4-yl-phenyl)-2-oxoethyl]-6-isopropoxy- [1,2,4]triazolo[4,3-b]pyridazin-1- iumtrifluoroacetate 1.35 483.3 (met. a) Ex.: 013

3-Amino-1-[2-(3-tert-butyl-4- methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-methoxy- [1,2,4]triazolo[4,3-b]pyridazin-1-iumtrifluoroacetate 1.24 455.1 (met. a) Ex.: 014

3-Amino-6-ethoxy-1-[2-(4- methoxy-3-morpholin-4-yl-5-trifluoromethylphenyl)-2- oxoethyl]-[1,2,4]triazolo[4,3-b]pyridazin-1-ium trifluoroacetate 1.17 481.1 (met. a) Ex.: 015

1-[2-(3-tert-butyl-4-methoxy-5- morpholin-4-ylphenyl)-2-oxoethyl]-6-ethoxy-3- ethoxycarbonylamino-[1,2,4]triazolo[4,3-b]pyridazin- 1-ium 1.34 541.3 (met. a) Ex.: 016

3-Amino-1-[2-(3-tert-butyl-4- methoxy-5-morpholin-4-yl-phenyl)-2-oxoethyl]-6- cyclopentyloxy-[1,2,4]triazolo[4,3-b]pyridazin-1- ium trifluoroacetate 1.42 509.2 (met.a) Ex.: 017

3-Amino-1-[2-(3-tert-butyl-4- methoxy-5-morpholin-4-yl-phenyl)-2-oxoethyl]-6- cyclobutoxy-[1,2,4]triazolo[4,3-b]pyridazin-1-ium trifluoroacetate 1.36 495.2 (met. a) Ex.: 018

3-Amino-1-[2-(3-tert-butyl-4- methoxy-5-morpholin-4-yl-phenyl)-2-oxoethyl]-6-phenoxy- [1,2,4]triazolo[4,3-b]pyridazin-1- iumtrifluoroacetate 1.34 517.3 (met. a) Ex.: 019

3- Amino-6-benzyloxy-1-[2-(3- tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]- [1,2,4]triazolo[4,3-b]pyridazin-1- iumtrifluoroacetate 1.39 531.2 (met. a) Ex.: 020

3-Amino-1-[2-(3-tert-butyl-4- methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-(1-ethyl- propoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium trifluoroacetate 1.46 511.2 (met. a) Ex.: 021

3-Amino-1-[2-(3-tert-butyl-4- methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6- cyclohexyloxy-[1,2,4]triazolo[4,3-b]pyridazin-1-ium trifluoroacetate 1.44 523.2 (met. a) Ex.: 022

3-Amino-1-[2-(3-tert-butyl-4- methoxy-5-morpholin-4-yl-phenyl)-2-oxoethyl]-6-(2,2,2- trifluoroethoxy)- [1,2,4]triazolo[4,3-b]pyridazin-1- ium trifluoroacetate 1.32 523.2 (met. a) Ex.: 023

3-Amino-1-[2-(3-tert-butyl-4- methoxy-5-morpholin-4-yl-phenyl)-2-oxoethyl]-6- cyclopropylmethoxy-[1,2,4]triazolo[4,3-b]pyridazin- 1-ium chloride hydrochloride 1.35 495.1(met. a) Ex.: 024

3-Acetylamino-1-[2-(3-tert-butyl- 4-methoxy-5-morpholin-4-yl-phenyl)-2-oxoethyl]-6-ethoxy- [1,2,4]triazolo[4,3- b]pyridazin-1-ium1.27 511.4 (met. a) Ex.: 025

3-Amino-6-(1-ethylpropoxy)-1- {2-[3-methylamino-5-(pentafluorosulfanyl)phenyl]-2- oxoethyl}-[1,2,4]triazolo[4,3-b]pyridazin-1-ium trifluoroacetate 1.32 495.1 (met. a) Ex.: 026

3-Amino-6-(1-ethylpropoxy)-1- {2-[3-methoxy-5-(pentafluorosulfanyl)phenyl]-2- oxoethyl}-[1,2,4]triazolo[4,3-b]pyridazin-1-ium trifluoroacetate 1.35 496.1 (met. a) Ex.: 027

3-Amino-1-[2-(3-tert-butyl-5- ethoxymethylphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)- [1,2,4]triazolo[4,3-b]pyridazin-1- ium chloride 0.91454.3 (met. b) Ex.: 028

3-Amino-1-[2-(3-tert-butyl-5- cyclopropylmethoxymethyl-phenyl)-2-oxoethyl]-6-(1- ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium chloride 1.51 480.1 (met. a) Ex.: 029

3-Amino-1-[2-(3-tert-butyl-4,5- diethoxyphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3- b]pyridazin-1-ium chloride 1.58 484.1(met. a) Ex.: 030

3-Amino-1-[2-(3-tert-butyl-4,5- bis-cyclopropylmethoxyphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)- [1,2,4]triazolo[4,3-b]pyridazin-1- iumchloride 1.64 536.5 (met. a) Ex.: 031

3-Amino-1-[2-(3-tert-butyl-5- propoxymethylphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)- [1,2,4]triazolo[4,3-b]pyridazin-1- iumchloride 0.94 468.2 (met. b) Ex.: 032

3-Amino-1-[2-(3-tert-butyl-5- ethoxyphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3- b]pyridazin-1-ium chloride 0.92 440.2(met. b) Ex.: 033

3-Amino-6-(1-ethylpropoxy)-1-[2- (3-methoxy-5- trifluoromethylphenyl)-2-oxoethyl]-[1,2,4]triazolo[4,3- b]pyridazin-1-ium trifluoroacetate 1.31438.1 (met. a) Ex.: 034

3-Amino-1-[2-(3-tert-butyl-5- methoxyphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3- b]pyridazin-1-ium chloride 0.89 426.2(met. b) Ex.: 035

3-Amino-1-[2-(3-tert-butyl-5- cyclopropylmethoxyphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)- [1,2,4]triazolo[4,3-b]pyridazin-1- iumchloride 0.95 466.3 (met. b) Ex.: 036

3-Amino-1-[2-(3-tert-butyl-5- cyclobutylmethoxyphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)- [1,2,4]triazolo[4,3-b]pyridazin-1- iumchloride 0.99 480.2 (met. b) Ex.: 037

3-Amino-1-[2-(3- benzyloxymethyl-5-tert- butylphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3- b]pyridazin-1-ium chloride 0.97 516.3(met. b) Ex.: 038

3-Amino-1-[2-(3- cyclohexylmethoxy-4,5- dimethoxyphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)- [1,2,4]triazolo[4,3-b]pyridazin-1- ium chloride 1.49512.5 (met. a) Ex.: 039

3-Amino-6-butoxy-1-[2-(3-tert- butyl-5-methoxymethylphenyl)-2-oxoethyl]-[1,2,4]triazolo[4,3- b]pyridazin-1-ium chloride 1.31 426.3(met. a) Ex.: 040

3-Amino-1-[2-(3-chloro-5- methoxyphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3- b]pyridazin-1-ium chloride 1.25 404.2(met. a) Ex.: 041

3-Amino-1-[2-(8-tert-butyl-4- methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-2- oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1- ium trifluoroacetate 1.41 467.3 (met.a) Ex.: 042

3-Amino-1-[2-(3-tert-butyl-4- methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6- diethylamino-[1,2,4]triazolo[4,3-b]pyridazin-1-ium trifluoroacetate 1.42 496.4 (met. a) Ex.: 043

3-Amino-1-[2-(3-tert-butyl-4- methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-piperidin- 1-yl-[1,2,4]triazolo[4,3-b]pyridazin-1-ium trifluoroacetate 1.35 508.3 (met. a) Ex.: 044

3-Amino-1-[2-(3- cyclohexylmethoxy-5- ethoxyphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3- b]pyridazin-1-ium chloride 1.00 496.3(met. b) Ex.: 045

3-Amino-1-[2-(3-bromo-5- methoxyphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3- b]pyridazin-1-ium chloride 0.82 448.1(met. b) Ex.: 046

3-Amino-6-(1-ethylpropoxy)-1-[2- (3-isopropyl-5-methoxyphenyl)-2-oxoethyl]-[1,2,4]triazolo[4,3- b]pyridazin-1-ium chloride 0.86 412.5(met. b) Ex.: 047

3-Amino-1-[2-(3- cyclohexylmethoxy-5- methoxyphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3- b]pyridazin-1-ium chloride 0.98 482.2(met. b) Ex.: 048

3-Amino-1-{2-[3-(3,3- dimethylbutoxy)-5-ethoxyphenyl]-2-oxoethyl}-6-(1-ethylpropoxy)- [1,2,4]triazolo[4,3-b]pyridazin-1- iumchloride 1.54 484.4 (met. a) Ex.: 049

3-Amino-1-[2-(8-tert-butyl-4- methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-2- oxoethyl]-6-ethoxy-[1,2,4]triazolo[4,3-a]pyridin-1- ium trifluoroacetate 1.22 424.2 (met.a) Ex.: 050

3-Amino-6-diethylamino-1-{2-[3- methoxy-5-(pentafluorosulfanyl)-phenyl]-2-oxoethyl}- [1,2,4]triazolo[4,3-b]pyridazin-1- iumtrifluoroacetate 1.27 481.1 (met. a) Ex.: 051

3-Amino-1-[2-(3-tert-butyl-4- methoxy-5-mopholin-4-ylphenyl)-2-oxoethyl]-6- morpholin-4-yl-[1,2,4]triazolo[4,3-b]pyridazin-1- ium trifluoroacetate 1.22 510.2 (met.a) Ex.: 052

3-Amino-1-[2-(5-bromo-2,3- dimethoxyphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)- [1,2,4]triazolo[4,3-b]pyridazin-1- ium chloride 1.32478.2 (met. a) Ex.: 053

3-Amino-1-[2-(3-chloro-4,5- dimethoxyphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)- [1,2,4]triazolo[4,3-b]pyridazin-1- ium chloride 1.29434.1 (met. a) Ex.: 054

3-Amino-1-{2-[3-tert-butyl-5-(2- methoxyethoxy)phenyl]-2-oxoethyl}-6-(1-ethylpropoxy)- [1,2,4]triazolo[4,3-b]pyridazin-1- iumchloride 1.40 470.3 (met. a) Ex.: 055

3-Amino-1-[2-(3-tert-butyl-5- methoxyphenyl)-2-oxoethyl]-6-(2-methoxyethoxy)- [1,2,4]triazolo[4,3-b]pyridazin-1- ium chloride 0.78414.2 (met. b) Ex.: 056

3-Amino-1-[2-(3-tert-butyl-5- methoxymethylphenyl)-2-oxoethyl]-6-(2-methoxyethoxy)- [1,2,4]triazolo[4,3-b]pyridazin-1- iumchloride 1.19 428.3 (met. a) Ex.: 057

3-Amino-1-[2-(3-tert-butyl-4- methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-chloro- [1,2,4]triazolo[4,3-b]pyridazin-1- iumtrifluoroacetate 1.45 459.2 (met. a) Ex.: 058

3-Amino-6-(1-ethylpropoxy)-1- {2-[3-morpholin-4-yl-5-(pentafluorosulfanyl)phenyl]-2- oxoethyl}-[1,2,4]triazolo[4,3-b]pyridazin-1- ium trifluoroacetate 1.33 551.2 (met. a) Ex.: 059

3-Amino-6-ethyl-1-{2-[3- methoxy-5- (pentafluorosulfanyl)phenyl]-2-oxoethyl}-[1,2,4]triazolo[4,3- b]pyridazin-1-ium trifluoroacetate 1.16438.0 (met. a) Ex.: 060

3-Amino-1-[2-(3-tert-butyl-4- methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-ethyl- [1,2,4]triazolo[4,3-b]pyridazin-1- iumtrifluoroacetate 1.24 453.3 (met. a) Ex.: 061

3-Amino-6-chloro-7- diethylcarbamoyl-1-{2-[3-methoxy-5-(pentafluorosulfanyl)- phenyl]-2-oxoethyl}-[1,2,4]triazolo[4,3-b]pyridazin-1- ium trifluoroacetate 1.46 543.1 (met.a) Ex.: 062

3-Amino-1-[2-(3-tert-butyl-4- methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-chloro-7- diethylcarbamoyl-[1,2,4]triazolo[4,3-b]pyridazin-1- ium trifluoroacetate 1.55 558.3 (met.a) Ex.: 063

3-Amino-7-diethylcarbamoyl-6- ethoxy-1-{2-[3-methoxy-5-(pentafluorosulfanyl)phenyl]-2- oxoethyl}-[1,2,4]triazolo[4,3-b]pyridazin-1-ium trifluoroacetate 1.24 553.2 (met. a) Ex.: 064

3-Amino-1-[2-(3-tert-butyl-4- methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-chloro-7- diethylamino-[1,2,4]triazolo[4,3-b]pyridazin-1-ium trifluoroacetate 1.37 530.2 (met. a) Ex.: 065

3-Amino-6-chloro-7- diethylamino-1-{2-[3-methoxy-5-(pentafluorosulfanyl)phenyl]-2- oxoethyl}-[1,2,4]triazolo[4,3-b]pyridazin-1-ium trifluoroacetate 1.28 515.0 (met. a) Ex.: 066

3-Amino-1-[2-(3-tert-butyl-4- methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-7- diethylcarbamoyl-6-ethoxy-[1,2,4]triazolo[4,3-b]pyridazin-1- ium trifluoroacetate 1.31 568.2 (met.a) Ex.: 067

3-Amino-7-diethylamino-6- ethoxy-1-{2-[3-methoxy-5-(pentafluorosulfanyl)phenyl]-2- oxoethyl}-[1,2,4]triazolo[4,3-b]pyridazin-1-ium trifluoroacetate 1.62 525.2 (met. a) Ex.: 068

3-Amino-8-diethylcarbamoyl-6- ethoxy-1-{2-[3-methoxy-5-(pentafluorosulfanyl)phenyl]-2- oxoethyl}-[1,2,4]triazolo[4,3-b]pyridazin-1-ium trifluoroacetate 1.26 553.2 (met. a) Ex.: 069

3-Amino-1-[2-(3-tert-butyl-4- methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6- diethylamino-8-methyl-[1,2,4]triazolo[4,3-b]pyridazin-1- ium trifluoroacetate 1.05 510.4 (met.b) Ex.: 070

3-Amino-6,7-diethoxy-1-{2-[3- morpholin-4-yl-5-(pentafluorosulfanyl)phenyl]-2- oxoethyl}-[1,2,4]triazolo[4,3-b]pyridazin-1-ium trifluoroacetate 0.96 553.2 (met. b) Ex.: 071

3-Amino-1-[2-(3-tert-butyl-4- methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6,7- diethoxy-[1,2,4]triazolo[4,3-b]pyridazin-1-ium trifluoroacetate 1.00 513.3 (met. b) Ex.: 072

1-[2-(3-tert-Butyl-4-methoxy-5- morpholin-4-ylphenyl)-2-oxoethyl]-6-ethoxy-7,8-dimethyl- 3-methylamino-[1,2,4]triazolo[4,3-b]pyridazin-1- ium trifluoroacetate 1.04 511.4 (met.b) Ex.: 073

3-Amino-1-[2-(3-tert-butyl-4- methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-7-ethyl-6- (1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1- ium trifluoroacetate 1.09 539.4 (met.b) Ex.: 074

3-Amino-1-[2-(3-tert-butyl-4- methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-ethoxy-7- ethyl-[1,2,4]triazolo[4,3-b]pyridazin-1-ium trifluoroacetate 1.03 497.3 (met. b) Ex.: 075

1-[2-(3-tert-Butyl-4-methoxy-5- morpholin-4-ylphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-7,8- dimethyl-3-methylamino-[1,2,4]triazolo[4,3-b]pyridazin-1- ium trifluoroacetate 1.11 553.4 (met.b) Ex.: 076

3-Amino-1-[2-(3-tert-butyl-4- methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-7- cyclopropyl-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1- ium chloride 1.10 551.4 (met. b) Ex.:077

3-Amino-1-[2-(3-tert-butyl-4- methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-(1- ethylpropoxy)-7-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-1- ium trifluoroacetate 1.12 553.4 (met.b) Ex.: 078

1-{2-[3-tert-Butyl-5-(2- hydroxyethoxy)phenyl]-2-oxoethyl}-6-ethoxy-7,8-dimethyl- 3-methylamino-[1,2,4]triazolo[4,3-b]pyridazin-1- ium chloride 0.95 456.3 (met. b) Ex.:079

1-{2-[3-tert-Butyl-5-(2- hydroxyethoxy)phenyl]-2-oxoethyl}-6-ethoxy-8-methyl-3- methylamino-[1,2,4]triazolo[4,3-b]pyridazin-1-ium chloride 0.93 442.3 (met. b) Ex.: 080

1-{2-[3-tert-Butyl-5-(3- hydroxypropoxy)-4-methoxyphenyl]-2-oxoethyl}-6- ethoxy-3-isopropylamino-7-methyl-[1,2,4]triazolo[4,3- b]pyridazin-1-ium chloride 1.03 514.4 (met.b) Ex.: 081

1-{2-[3-tert-Butyl-5-(3- hydroxypropoxy)-4-methoxyphenyl]-2-oxoethyl}-3- cyclopropylamino-6-ethoxy-7,8-dimethyl-[1,2,4]triazolo[4,3- b]pyridazin-1-ium chloride 1.03 526.4(met. b) Ex.: 082

3-Amino-1-{2-[3-tert-butyl-5-(3- hydroxypropoxy)-4-methoxyphenyl]-2-oxoethyl}-6- ethoxy-7-ethyl-[1,2,4]triazolo[4,3-b]pyridazin-1-ium chloride 0.97 486.3 (met. b) Ex.: 083

3-Amino-1-{2-[3-tert-butyl-5-(2- hydroxyethoxy)phenyl]-2-oxoethyl}-8-methyl-6-(oxetan-3- yloxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium chloride 1.08 456.2 (met. a) Ex.: 084

1-{2-[3-tert-Butyl-5-(3- hydroxypropoxy)-4-methoxyphenyl]-2-oxoethyl}-6- ethoxy-7,8-dimethyl-3-(2,2,2-trifluoroethylamino)- [1,2,4]triazolo[4,3-b]pyridazin-1- ium chloride1.02 568.3 (met. b) Ex.: 085

1-{2-[3-tert-Butyl-5-(2- hydroxyethoxy)phenyl]-2-oxo-ethyl}-6-ethoxy-7,8-dimethyl-3- (2,2,2-trifluoroethylamino)-[1,2,4]triazolo[4,3-b]pyridazin-1- ium chloride 0.99 524.3 (met. b) Ex.:086

1-{2-[3-tert-Butyl-5-(2- hydroxyethoxy)-4- methoxyphenyl]-2-oxoethyl}-6-dimethylcarbamoyl-8-methyl-3- methylamino-[1,2,4]triazolo[4,3-b]pyridazin-1-ium chloride 0.74 499.2 (met. b)

Pharmacological Examples

PAR1 determination method: inhibition of PAR1-mediated plateletaggregation The pharmacological testing of the substances took place inplatelet aggregation induced by TRAP (thrombin receptor-activatingpeptide) in 96-well format. For this purpose, blood was taken fromhealthy volunteer donors in 20 ml syringes containing 2 ml of 3.13%sodium citrate solution. After centrifugation at 150×g for 20 minutes,the platelet-rich plasma (PRP) was separated off and mixed with 1 μl ofPGE1 solution (500 μg/ml in ethanol)/ml of PRP. Incubation at RT for 5minutes was followed by centrifugation at 120×g for 15 minutes to removethe leukocytes. The leukocyte-free PRP was transferred in 5 ml portionsinto 15 ml PP tubes and centrifuged at 360×g for 15 minutes in order topellet the platelets. The plasma was then decanted off and the plateletsediment from 5 ml of PRP was resuspended in 1 ml of Tyrode's (120 mMNaCl, 2.6 mM KCl, 12 mM NaHCO₃, 0.39 mM NaH₂PO₄×H₂O, 10 mM HEPES, 0.35%BSA, 5.5 mM glucose, pH 7.4) and adjusted with Tyrode's to a plateletcount of 3×10⁵/microliter (1 L). 13 ml of this cell suspension were thenmixed with 866 μL of 10 mM CaCl₂ solution, and 120 μL thereof werepipetted into each well of a 96-well plate containing 15 μL of thesubstance to be tested. After incubation at RT in the dark for 30minutes, 15 μL of a TRAP solution (70-100 μM) were added as agonist, andkinetics were recorded at 650 nm in a SpectraMax 340 at 37° C. for 20minutes while shaking The areas under the curves of negative control(Tyrode's/DMSO) and positive control (15 μl of agonist/DMSO) werecalculated and the difference was fixed as the 100% value. Thesubstances to be tested were pipetted as serial dilutions in duplicatedetermination, the AUC was likewise determined for each substanceconcentration, and the % inhibition of the AUC compared with the controlwas calculated. On the basis of the % inhibition, the IC₅₀ wascalculated by nonlinear regression analysis according to the 4-parameterequation. Table 1 shows the results.

TABLE 1 Compound Inhibition of platelet Compound Inhibition of plateletfrom aggregation from aggregation example IC₅₀ [micro M] example IC₅₀[micro M] 1 <0.014 3 1.08 4 0.126 8 4.4 26 0.005 32 0.006 38 0.24 390.037

PAR1 Binding Test

The synthesized substances were examined in a PAR1 binding test. Thistested whether the substances can inhibit the binding of a radioactivelylabeled PAR1 agonist known from the literature at the PAR1 receptor(Ho-Sam Ahn, Mol Pharm, 51:350-356, 1997).

The human PAR1 receptor was expressed transiently in High Five insectcells. From these cells, after 48 hours, a membrane preparation wasproduced by standard methods, aliquoted into 10 mM Tris-HCl; 0.3 mMEDTA; 1 mM EGTA; 250 mM sucrose pH 7.5, and stored at −80° C.

The substances were preincubated with the membrane at RT for 15 minutes,then the radioligand (ALA-(para-F-Phe)-Arg-ChA-homoArg-(3,4⁻³H-Tyr)-NH₂;approx. 40 Ci/mMol) was added. The end concentration of the radioligandin the test buffer (50 mM Tris-HCl; 10 mM MgCl₂; 1 mM EGTA; 0.1% BSA; 2%DMSO) was 20 nM, that of the membrane 1 mg/ml. After an incubation timeof 60 minutes, 25 μL of the mixture were transferred to a 96-wellMultiScreenHTS FB microtiter filtration plate (from Millipore), whichhad been pretreated beforehand with a 0.75% aqueous polyethyleneiminesolution for 5 hours at RT. Thereafter, with vacuum extraction, eachwell was washed four times with 300 μL of buffer (50 mM Tris-HCl; 10 mMMgCl₂; 1 mM EGTA). The plate was then dried overnight, 100 μl ofscintillator per well were added, and the plate was analyzed after 6hours in a Wallac MicroBeta (from PerkinElmer) liquid scintillationcounter. The nonspecific binding was determined in the presence of 100μM SCH79797 (PAR-1 antagonist; from Tocris, Cat. No. 1592) andsubtracted from all measurements. The 100% value used was a controlwithout inhibitor. The % inhibition values of a substance dilutionseries were used to calculate the IC₅₀ with the aid of nonlinearregression analysis according to the 4-parameter equation.

Table 2 shows the results.

TABLE 2 Compound from Inhibition of binding Compound from Inhibition ofbinding example IC₅₀ [micro M] example IC₅₀ [micro M] 27 0.152 54 0.08529 0.136 60 2.1 35 0.132 72 1.7 40 0.601 76 1.4 46 0.114 82 8.4 47 10

1. A compound of formula I

or a stereoisomeric or tautomeric form thereof, or a physiologicallycompatible salt of any of them, where X is C—R1 or N, A⁻ is an anion ofan organic or inorganic acid, Q1 is a hydrogen atom, —(C₁-C₆)-alkyl,—(C₃-C₆)-cycloalkyl, —(C₀-C₄)-alkylene-C(O)—O—R11,—(C₀-C₄)-alkylene-C(O)—N(R11)-R12, —(C₀-C₄)-alkylene-C(O)—R11, —OH, —O—(C₁-C₆)-alkyl or —O—(C₃-C₆)-cycloalkyl, where alkyl and cycloalkyl areeach unsubstituted or mono-, di- or trisubstituted independently by—(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl or—O—(C₃-C₆)-cycloalkyl, where some or all of the hydrogen atoms in alkylor cycloalkyl may be replaced by fluorine, Q2 and Q3 are the same ordifferent and are each independently a hydrogen atom, —(C₁-C₆)-alkyl or—(C₃-C₆)-cycloalkyl, where some or all of the hydrogen atoms in alkyl orcycloalkyl may be replaced by fluorine, R1, R2, R3 and R4 are the sameor different and are each independently a hydrogen atom, —(C₁-C₆)-alkyl,—(C₃-C₆)-cycloalkyl, —O—(C₁-C₈)-alkyl, —O—(C₃-C₆)-cycloalkyl,—(C₀-C₄)-alkylene-C(O)—N(R11)-R12, —(C₀-C₄)-alkylene-C(O)—O—R11,—(C₀-C₄)-alkylene-N(R11)—C(O)—O—R12, —(C₀-C₄)-alkylene-C(O)—R11,—(C₀-C₄)-alkylene-N(R11)-R12, —(C₀-C₄)-alkylene-N(R11)-C(O)—R12,halogen, OH, —CN, —NO₂, —SO₂CH₃, —SO₂CF₃, —SF₅, —Si[—(C₁-C₄)-alkyl]₃,—(C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl, —O—(C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl,—O—(C₀-C₄)-alkylene-(C₆-C₁₄)-aryl where aryl is unsubstituted or mono-,di- or trisubstituted independently by —O—(C₁-C₆)-alkyl, —(C₁-C₄)-alkyl,OH, —(C₃-C₆)-cycloalkyl or —O—(C₃-C₆)-cycloalkyl,—O—(C₁-C₄)-alkylene-(C₃-C₆)-cycloalkyl, —(C₄-C₁₅)-Het where Het isunsubstituted or mono-, di- or trisubstituted independently by—(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl or—O—(C₃-C₆)-cycloalkyl or—O—(C₁-C₆)-alkylene-O—(C₁-C₆)-alkylene-β-(C₁-C₆)-alkyl, where alkyl,alkylene and cycloalkyl are each unsubstituted or mono-, di- ortrisubstituted independently by —(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH,—O —(C₁-C₆)-alkyl, —(C₆-C₁₄)-aryl where aryl is unsubstituted or mono-,di-, tri-, tetra- or pentasubstituted independently by halogen,—(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl or—O—(C₃-C₆)-cycloalkyl, —(C₄-C₁₅)-Het where Het is unsubstituted ormono-, di-, tri-, tetra- or pentasubstituted independently by halogen,—(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl or—O—(C₃-C₆)-cycloalkyl, or —O—(C₃-C₆)-cycloalkyl, where some or all ofthe hydrogen atoms in alkyl, alkylene or cycloalkyl may be replaced byfluorine, or R1 and R2, R2 and R3 or R3 and R4, together with the ringatoms to which they are each bonded, form a 5- to 8-membered ring, wherethe ring consists only of carbon atoms or 1, 2 or 3 of these atoms arereplaced by nitrogen, oxygen or sulfur atoms, where the ring isunsubstituted or mono- or disubstituted independently by —(C₁-C₄)-alkyl,—(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl or —O—(C₃-C₆)-cycloalkyl,where some or all of the hydrogen atoms in the 5- to 8-membered ringformed, and in alkyl or cycloalkyl, may be replaced by fluorine, R11 andR12 (should also apply to Q1!) are each independently a hydrogen atom,—(C₁-C₆)-alkyl, —(C₃-C₆)-cycloalkyl, —(C₀-C₄)-alkylene-(C₆-C₁₄)-aryl,—(C₀-C₄)-alkylene-(C₄-C₁₅)-Het, —SO₂CH₃ or —SO₂CF₃, where some or all ofthe hydrogen atoms in alkyl, alkylene or cycloalkyl may be replaced byfluorine, or R11 and R12 in the “N(R11)-R12” and “N(R11)-C(O)—R12”fragments represent a 5- to 8-membered ring which is formed togetherwith the nitrogen atom “N” or the “N—C(O)” group to form cyclic amines,imides or lactams which contain up to 2 further heteroatoms from thegroup of N, O and S, where the ring is unsubstituted or mono- ordisubstituted independently by —(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH,—O—(C₁-C₆)-alkyl or —O—(C₃-C₆)-cycloalkyl, where some or all of thehydrogen atoms in the 5- to 8-membered ring formed, and in alkyl orcycloalkyl, may be replaced by fluorine, R5, R6, R7, R8 and R9 are thesame or different and are each independently a hydrogen atom,—(C₁-C₆)-alkyl, —(C₃-C₆)-cycloalkyl, OH, —CN, —NO₂, —O—(C₁-C₈)-alkyl,—O—(C₃-C₆)-cycloalkyl, —(C₀-C₄)-alkylene-(CO)—N(R21)-R22, —SO₂CH₃,—SO₂CF₃, —(C₀-C₄)-alkylene-C(O)—O—R21, halogen, —SF₅,—(C₀-C₄)-alkylene-C(O)—R21, —(C₀-C₄)-alkylene-N(R21)-R22,—(C₀-C₄)-alkylene-N(R21)-C(O)—R22, —(C₁-C₆)-alkylene-β-(C₁-C₆)-alkyl,—Si[—(C₁-C₄)-alkyl]₃,—(C₀-C₆)-alkylene-O—(C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl, —(C₄-C₁₅)-Het,—(C₀-C₆)-alkylene-O—(C₁-C₄)-alkylene-(C₃-C₆)-cycloalkyl or—(C₀-C₆)-alkylene-O—(C₀-C₆)-alkylene-(C₆-C₁₄)-aryl, where alkyl,alkylene and cycloalkyl are each unsubstituted or mono-, di- ortrisubstituted independently by —(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH,—O—(C₁-C₆)-alkyl, —(C₆-C₁₄)-aryl where aryl is unsubstituted or mono-,di-, tri-, tetra- or pentasubstituted independently by halogen,—(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl or—O—(C₃-C₆)-cycloalkyl, —(C₄-C₁₅)-Het where Het is unsubstituted ormono-, di-, tri-, tetra- or pentasubstituted independently by halogen,—(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl or—O—(C₃-C₆)-cycloalkyl, or —O—(C₃-C₆)-cycloalkyl, where some or all ofthe hydrogen atoms in alkyl, alkylene or cycloalkyl may be replaced byfluorine, or R5 and R6, R6 and R7, R7 and R8 or R8 and R9, together withthe ring atoms to which they are each bonded, form a 5- to 8-memberedring, where the ring consists only of carbon atoms or 1, 2 or 3 of theseatoms are replaced by nitrogen, oxygen or sulfur atoms, where the ringis unsubstituted or mono- or disubstituted independently by—(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl or—O—(C₃-C₆)-cycloalkyl, where some or all of the hydrogen atoms in the 5-to 8-membered ring formed, and in alkyl or cycloalkyl, may be replacedby fluorine, R21 and R22 are each independently a hydrogen atom,—(C₁-C₆)-alkyl, —(C₃-C₆)-cycloalkyl, —(C₀-C₄)-alkylene-(C₆-C₁₄)-aryl,—(C₀-C₄)-alkylene-(C₄-C₁₅)-Het, —SO₂CH₃ or —SO₂CF₃, where some or all ofthe hydrogen atoms in alkyl, alkylene or cycloalkyl may be replaced byfluorine, or R21 and R22 in the “N(R21)-R22” and “N(R21)-C(O)—R22”fragments represent a 5- to 8-membered ring which is formed togetherwith the nitrogen atom “N” or the “N—C(O)” group to form cyclic amines,imides or lactams which contain up to 2 further heteroatoms from thegroup of N, O and S, where the ring is unsubstituted or mono- ordisubstituted independently by —(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH,—O—(C₁-C₆)-alkyl or —O—(C₃-C₆)-cycloalkyl, where some or all of thehydrogen atoms in the 5- to 8-membered ring formed, and in alkyl orcycloalkyl, may be replaced by fluorine.
 2. A compound as claimed inclaim 1, wherein X is C—R1 or N, A⁻ is an anion of an organic orinorganic acid, Q1 is a hydrogen atom, —(C₁-C₆)-alkyl,—(C₃-C₆)-cycloalkyl, —(C₀-C₄)-alkylene-C(O)-β—R11,—(C₀-C₄)-alkylene-C(O)—N(R11)-R12, —(C₀-C₄)-alkylene-C(O)—R11, —OH,—O—(C₁-C₆)-alkyl or —O—(C₃-C₆)-cycloalkyl, where alkyl and cycloalkylare each unsubstituted or mono-, di- or trisubstituted independently by—(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl or—O—(C₃-C₆)-cycloalkyl, where some or all of the hydrogen atoms in alkylor cycloalkyl may be replaced by fluorine, Q2 and Q3 are the same ordifferent and are each independently a hydrogen atom, —(C₁-C₆)-alkyl or—(C₃-C₆)-cycloalkyl, where some or all of the hydrogen atoms in alkyl orcycloalkyl may be replaced by fluorine, R1, R2, R3 and R4 are the sameor different and are each independently a hydrogen atom, —(C₁-C₆)-alkyl,—(C₃-C₆)-cycloalkyl, —O—(C₁-C₈)-alkyl, —O—(C₃-C₆)-cycloalkyl,—(C₀-C₄)-alkylene-C(O)—N(R11)-R12, —(C₀-C₄)-alkylene-N(R11)-C(O)—O—R12,—(C₀-C₄)-alkylene-C(O)—O—R11, —(C₀-C₄)-alkylene-C(O)—R11,—(C₀-C₄)-alkylene-N(R11)-R12, —(C₀-C₄)-alkylene-N(R11)-C(O)—R12,halogen, OH, —CN, —NO₂, —SO₂CH₃, —SO₂CF₃, —SF₅, —Si[—(C₁-C₄)-alkyl]₃,—(C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl, —O—(C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl,—O—(C₀-C₄)-alkylene-(C₆-C₁₄)-aryl where aryl is unsubstituted or mono-,di- or trisubstituted independently by —O—(C₁-C₆)-alkyl, —(C₁-C₄)-alkyl,OH, —(C₃-C₆)-cycloalkyl or —O—(C₃-C₆)-cycloalkyl,—O—(C₁-C₄)-alkylene-(C₃-C₆)-cycloalkyl, —(C₄-C₁₅)-Het where Het isunsubstituted or mono-, di- or trisubstituted independently by—(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl or—O—(C₃-C₆)-cycloalkyl, or—O—(C₁-C₆)-alkylene-O—(C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl, where alkyl,alkylene and cycloalkyl are each unsubstituted or mono-, di- ortrisubstituted independently by —(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH,—O—(C₁-C₆)-alkyl, —(C₆-C₁₄)-aryl where aryl is unsubstituted or mono-,di-, tri-, tetra- or pentasubstituted independently by halogen,—(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl or—O—(C₃-C₆)-cycloalkyl, —(C₄-C₁₅)-Het where Het is unsubstituted ormono-, di-, tri-, tetra- or pentasubstituted independently by halogen,—(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl or—O—(C₃-C₆)-cycloalkyl, or —O—(C₃-C₆)-cycloalkyl, where some or all ofthe hydrogen atoms in alkyl, alkylene or cycloalkyl may be replaced byfluorine, with the proviso that at least one R1, R2, R3 or R4 is not ahydrogen atom or R1 and R2, R2 and R3 or R3 and R4, together with thering atoms to which they are each bonded, form a 5- to 8-membered ring,where the ring consists only of carbon atoms or 1, 2 or 3 of these atomsare replaced by nitrogen, oxygen or sulfur atoms, where the ring isunsubstituted or mono- or disubstituted independently by —(C₁-C₄)-alkyl,—(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl or —O—(C₃-C₆)-cycloalkyl,where some or all of the hydrogen atoms in the 5- to 8-membered ringformed, and in alkyl or cycloalkyl, may be replaced by fluorine, R11 andR12 are each independently a hydrogen atom, —(C₁-C₆)-alkyl,—(C₃-C₆)-cycloalkyl, —(C₀-C₄)-alkylene-(C₆-C₁₄)-aryl,—(C₀-C₄)-alkylene-(C₄-C₁₅)—Het, —SO₂CH₃ or —SO₂CF₃, where some or all ofthe hydrogen atoms in alkyl, alkylene or cycloalkyl may be replaced byfluorine, or R11 and R12 in the “N(R11)-R12” and “N(R11)-C(O)—R12”fragments represent a 5- to 8-membered ring which is formed togetherwith the nitrogen atom “N” or the “N—(CO)” group to form cyclic amines,imides or lactams which contain up to 2 further heteroatoms from thegroup of N, O and S, where the ring is unsubstituted or mono- ordisubstituted independently by —(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH,—O—(C₁-C₆)-alkyl or —O—(C₃-C₆)-cycloalkyl, where some or all of thehydrogen atoms in the 5- to 8-membered ring formed, and in alkyl orcycloalkyl, may be replaced by fluorine, R4, R5, R6, R7, R8 and R9 arethe same or different and are each independently a hydrogen atom,—(C₁-C₆)-alkyl, —(C₃-C₆)-cycloalkyl, OH, —CN, —NO₂, —O—(C₁-C₈)-alkyl,—O—(C₃-C₆)-cycloalkyl, —(C₀-C₄)-alkylene-(CO)—N(R21)-R22, —SO₂CH₃,—SO₂CF₃, —(C₀-C₄)-alkylene-C(O)—O—R21, halogen, —SF₅,—(C₀-C₄)-alkylene-C(O)—R21, —(C₀-C₄)-alkylene-N(R21)-R22,—(C₀-C₄)-alkylene-N(R21)-C(O)—R22, —(C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl,—(C₀-C₆)-alkylene-O—(C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl,—Si[—(C₁-C₄)-alkyl]₃,—(C₀-C₆)-alkylene-O—(C₁-C₄)-alkylene-(C₃-C₆)-cycloalkyl,—(C₀-C₆)-alkylene-O—(C₀-C₆)-alkylene-(C₆-C₁₄)-aryl or —(C₄-C₁₅)-Het,where alkyl, alkylene and cycloalkyl are each unsubstituted or mono-,di- or trisubstituted independently by —(C₁-C₄)-alkyl,—(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl, —(C₆-C₁₄)-aryl where aryl isunsubstituted or mono-, di-, tri-, tetra- or pentasubstitutedindependently by halogen, —(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH,—O—(C₁-C₆)-alkyl or —O—(C₃-C₆)-cycloalkyl, —(C₄-C₁₅)-Het where Het isunsubstituted or mono-, di-, tri-, tetra- or pentasubstitutedindependently by halogen, —(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH,—O—(C₁-C₆)-alkyl or —O—(C₃-C₆)-cycloalkyl, or —O—(C₃-C₆)-cycloalkyl,where some or all of the hydrogen atoms in alkyl, alkylene or cycloalkylmay be replaced by fluorine, with the proviso that at least one R5, R6,R7, R8 or R9 is not a hydrogen atom, or R5 and R6, R6 and R7, R7 and R8or R8 and R9, together with the ring atoms to which they are eachbonded, form a 5- to 8-membered ring, where the ring consists only ofcarbon atoms or 1, 2 or 3 of these atoms are replaced by nitrogen,oxygen or sulfur atoms, where the ring is unsubstituted or mono- ordisubstituted independently by —(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH,—O—(C₁-C₆)-alkyl or —O—(C₃-C₆)-cycloalkyl, where some or all of thehydrogen atoms in the 5- to 8-membered ring formed, and in alkyl orcycloalkyl, may be replaced by fluorine, R21 and R22 are eachindependently a hydrogen atom, —(C₁-C₆)-alkyl, —(C₃-C₆)-cycloalkyl,—(C₀-C₄)-alkylene-(C₆-C₁₄)-aryl, —(C₀-C₄)-alkylene-(C₄-C₁₅)—Het, —SO₂CH₃or —SO₂CF₃, where some or all of the hydrogen atoms in alkyl, alkyleneor cycloalkyl may be replaced by fluorine, or R21 and R22 in the“N(R21)-R22” and “N(R21)-C(O)—R22” fragments represent a 5- to8-membered ring which is formed together with the nitrogen atom “N” orthe “N—C(O)” group to form cyclic amines, imides or lactams whichcontain up to 2 further heteroatoms from the group of N, O and S, wherethe ring is unsubstituted or mono- or disubstituted independently by—(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl or—O—(C₃-C₆)-cycloalkyl, where some or all of the hydrogen atoms in the 5-to 8-membered ring formed, and in alkyl or cycloalkyl, may be replacedby fluorine.
 3. A compound as claimed in claim 1, wherein X is C—R1 orN, A⁻ is an anion of an organic or inorganic acid, Q1 is a hydrogenatom, —(C₁-C₆)-alkyl, —(C₃-C₆)-cycloalkyl, —(C₀-C₄)-alkylene-C(O)—O—R11,—(C₀-C₄)-alkylene-C(O)—N(R11)-R12, —(C₀-C₄)-alkylene-C(O)—R11, —OH,—O—(C₁-C₆)-alkyl or —O—(C₃-C₆)-cycloalkyl, where alkyl and cycloalkylare each unsubstituted or mono-, di- or trisubstituted independently by—(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl or—O—(C₃-C₆)-cycloalkyl, where some or all of the hydrogen atoms in alkylor cycloalkyl may be replaced by fluorine, Q2 and Q3 are the same ordifferent and are each independently a hydrogen atom, —(C₁-C₆)-alkyl or—(C₃-C₆)-cycloalkyl, where some or all of the hydrogen atoms in alkyl orcycloalkyl may be replaced by fluorine, R1, R2, R3 and R4 are the sameor different and are each independently a hydrogen atom, —(C₁-C₆)-alkyl,—(C₃-C₆)-cycloalkyl, —O—(C₁-C₈)-alkyl, —O—(C₃-C₆)-cycloalkyl,—(C₀-C₄)-alkylene-C(O)—N(R11)-R12, —(C₀-C₄)-alkylene-C(O)—O—R11,—(C₀-C₄)-alkylene-N(R11)-C(O)—O—R12, —(C₀-C₄)-alkylene-C(O)—R11,—(C₀-C₄)-alkylene-N(R11)-R12, —(C₀-C₄)-alkylene-N(R11)-C(O)—R12,halogen, OH, —CN, —NO₂, —SO₂CH₃, —Si[—(C₁-C₄)-alkyl]₃,—(C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl, —O—(C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl,—O—(C₀-C₄)-alkylene-(C₆-C₁₄)-aryl,—O—(C₁-C₄)-alkylene-(C₃-C₆)-cycloalkyl, —(C₄-C₁₅)-Het or—O—(C₁-C₆)-alkylene-O—(C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl, where alkyl,alkylene and cycloalkyl are each unsubstituted or mono-, di- ortrisubstituted independently by —(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH,—O—(C₁-C₆)-alkyl or —O—(C₃-C₆)-cycloalkyl, where some or all of thehydrogen atoms in alkyl, alkylene or cycloalkyl may be replaced byfluorine, with the proviso that at least one R1, R2, R3 or R4 is not ahydrogen atom or R1 and R2, R2 and R3 or R3 and R4, together with thering atoms to which they are each bonded, form a ring selected from thegroup of2,3,5,6,7,8-hexahydro-1,2,3a,4,5,8-hexaaza-cyclopenta[b]naphthalene;2,6,7,8-tetrahydro-3H-5-oxa-1,2,3a,4,8-pentaaza-cyclopenta[b]naphthalene;2,3,6,7-tetrahydro-5,8-dioxa-1,2,3a,4-tetraaza-cyclopenta[b]naphthalene;2,3,6,7-tetrahydro-5H-8-oxa-1,2,3a,4,5-pentaaza-cyclopenta[b]naphthalene;2,6,7,8-tetrahydro-3H-5-thia-1,2,3a,4,8-pentaaza-cyclopenta[b]naphthalene;2,3,6,7,8,9-hexahydro-1,2,3a,4,6,9-hexaazacyclopenta[a]-naphthalene;2,3-dihydro-5,7-dioxa-1,2,3a,4-tetraaza-s-indacene;2,6,7,8-tetrahydro-3H-cyclopenta[e][1,2,4]triazolo[4,3-b]pyridazine;2,7,8,9-tetrahydro-3H-cyclopenta[d][1,2,4]triazolo[4,3-b]pyridazine and2,3,6a,9a-tetrahydro-[1,3]dioxolo[4,5-d][1,2,4]triazolo[4,3-b]pyridazine,where the ring is unsubstituted or mono- or disubstituted independentlyby —(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH, —O —(C₁-C₆)-alkyl or—O—(C₃-C₆)-cycloalkyl, where some or all of the hydrogen atoms in the 5-to 8-membered ring formed, and in alkyl or cycloalkyl, may be replacedby fluorine, R11 and R12 are each independently a hydrogen atom,—(C₁-C₆)-alkyl, —(C₃-C₆)-cycloalkyl, —(C₀-C₄)-alkylene-(C₆-C₁₄)-aryl,—(C₀-C₄)-alkylene-(C₄-C₁₅)-Het, —SO₂CH₃ or —SO₂CF₃, where some or all ofthe hydrogen atoms in alkyl, alkylene or cycloalkyl may be replaced byfluorine, or R11 and R12 in the “N(R11)-R12” and “N(R11)-C(O)—R12”fragments represent a 5- to 8-membered ring, selected from the group ofazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepinyl,morpholinyl, thiomorpholinyl, pyrrolidine-2,5-dionyl,piperidine-2,6-dionyl, piperazine-2,6-dionyl, morpholine-3,5-dionyl,pyrrolidin-2-onyl, piperidin-2-onyl, piperazin-2-onyl andmorpholin-3-onyl, where the ring is unsubstituted or mono- ordisubstituted independently by —(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH,—O—(C₁-C₆)-alkyl or —O—(C₃-C₆)-cycloalkyl, where some or all of thehydrogen atoms in the 5- to 8-membered ring formed, and in alkyl orcycloalkyl, may be replaced by fluorine, R4, R5, R6, R7, R8 and R9 arethe same or different and are each independently a hydrogen atom,—(C₁-C₆)-alkyl, —(C₃-C₆)-cycloalkyl, OH, —CN, —NO₂, —O—(C₁-C₈)-alkyl,—O—(C₃-C₆)-cycloalkyl, —SO₂CH₃, —SO₂CF₃,—(C₀-C₄)-alkylene-(CO)—N(R21)-R22, —(C₀-C₄)-alkylene-C(O)—O—R21,halogen, —SF₅, —(C₀-C₄)-alkylene-C(O)—R21, —(C₀-C₄)-alkylene-N(R21)-R22,—(C₀-C₄)-alkylene-N(R21)-C(O)—R22, —(C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl,—(C₀-C₆)-alkylene-O—(C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl,—Si[—(C₁-C₄)-alkyl]₃,—(C₀-C₆)-alkylene-O—(C₁-C₄)-alkylene-(C₃-C₆)-cycloalkyl,—(C₀-C₆)-alkylene-O—(C₀-C₆)-alkylene-(C₆-C₁₄)-aryl or —(C₄-C₁₅)-Het,where alkyl, alkylene and cycloalkyl are each unsubstituted or mono-,di- or trisubstituted independently by —(C₁-C₄)-alkyl,—(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl, —(C₆-C₁₄)-aryl where aryl isunsubstituted or mono-, di-, tri-, tetra- or pentasubstitutedindependently by halogen, —(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH,—O—(C₁-C₆)-alkyl or —O—(C₃-C₆)-cycloalkyl, —(C₄-C₁₅)-Het where Het isunsubstituted or mono-, di-, tri-, tetra- or pentasubstitutedindependently by halogen, —(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH,—O—(C₁-C₆)-alkyl or —O—(C₃-C₆)-cycloalkyl, or —O—(C₃-C₆)-cycloalkyl,where some or all of the hydrogen atoms in alkyl, alkylene or cycloalkylmay be replaced by fluorine, with the proviso that at least one R5, R6,R7, R8 or R9 is not a hydrogen atom, or R5 and R6, R6 and R7, R7 and R8or R8 and R9, together with the ring atoms to which they are eachbonded, form a 5- to 8-membered ring selected from the group of2,3-dihydrobenzo[1,4]dioxin; 3,4-dihydro-2H-benzo[1,4]oxazine;1,2,3,4-tetrahydroquinoxaline; benzo[1,3]dioxole;3,4-dihydro-2H-benzo[1,4]thiazine and2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine, where the ring isunsubstituted or mono- or disubstituted independently by —(C₁-C₄)-alkyl,—(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl or —O—(C₃-C₆)-cycloalkyl,where some or all of the hydrogen atoms in the 5- to 8-membered ringformed, and in alkyl or cycloalkyl, may be replaced by fluorine, R21 andR22 are each independently a hydrogen atom, —(C₁-C₆)-alkyl,—(C₃-C₆)-cycloalkyl, —(C₀-C₄)-alkylene-(C₆-C₁₄)-aryl,—(C₀-C₄)-alkylene-(C₄-C₁₅)-Het, —SO₂CH₃ or —SO₂CF₃, where some or all ofthe hydrogen atoms in alkyl, alkylene or cycloalkyl may be replaced byfluorine, or R21 and R22 in the “N(R21)-R22” and “N(R21)-C(O)—R22”fragments represent a 5- to 8-membered ring selected from the group ofazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepinyl,morpholinyl, thiomorpholinyl, pyrrolidine-2,5-dionyl,piperidine-2,6-dionyl, piperazine-2,6-dionyl, morpholine-3,5-dionyl,pyrrolidin-2-onyl, piperidin-2-onyl, piperazin-2-onyl andmorpholin-3-onyl, where the ring is unsubstituted or mono- ordisubstituted independently by —(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH,—O —(C₁-C₆)-alkyl or —O—(C₃-C₆)-cycloalkyl, where some or all of thehydrogen atoms in the 5- to 8-membered ring formed, and in alkyl orcycloalkyl, may be replaced by fluorine.
 4. A compound as claimed inclaim 1, wherein X is C—R1 or N, A⁻ is an anion of an organic orinorganic acid, Q1 is a hydrogen atom, —(C₁-C₆)-alkyl,—(C₃-C₆)-cycloalkyl, —(C₀-C₄)-alkylene-C(O)—O—R11,—(C₀-C₄)-alkylene-C(O)—N(R11)-R12, —(C₀-C₄)-alkylene-C(O)—R11, —OH,—O—(C₁-C₆)-alkyl or —O—(C₃-C₆)-cycloalkyl, where alkyl and cycloalkylare each unsubstituted or mono-, di- or trisubstituted independently by—(C₁-C₄)-alkyl, —(C₃-C₆)-cycloalkyl, OH, —O—(C₁-C₆)-alkyl or—O—(C₃-C₆)-cycloalkyl, where some or all of the hydrogen atoms in alkylor cycloalkyl may be replaced by fluorine, Q2 and Q3 are the same ordifferent and are each independently a hydrogen atom, —(C₁-C₆)-alkyl or—(C₃-C₆)-cycloalkyl, where some or all of the hydrogen atoms in alkyl orcycloalkyl may be replaced by fluorine, R1, R2, R3 and R4 are the sameor different and are each independently a hydrogen atom, —(C₁-C₄)-alkyl,—O—(C₁-C₈)-alkyl, —O—(C₃-C₆)-cycloalkyl,—(C₀-C₄)-alkylene-C(O)—N(R11)-R12, —(C₀-C₄)-alkylene-C(O)—O—R11, —CF₃,—(C₀-C₄)-alkylene-N(R11)-C(O)—O—R12, —(C₀-C₄)-alkylene-N(R11)-R12,chlorine, —O —(C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl,—O—(C₀-C₄)-alkylene-(C₆-C₁₄)-aryl or —(C₄-C₁₅)-Het where Het is selectedfrom the group of acridinyl, azepinyl, azetidinyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzothiazolyl, benzotriazolyl, benzisoxazolyl, benzisothiazolyl,carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, dibenzofuranyl, dibenzothiophenyl,dihydrofuran[2,3-b]tetrahydrofuranyl, dihydrofuranyl, dioxolyl,dioxanyl, 2H, 6H-1,5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl,3H-indolyl, isobenzofuranyl, isoquinolinyl, isochromanyl, isoindazolyl,isoindolinyl, isoindolyl, isothiazolidinyl, 2-isothiazolinyl,isothiazolyl, isoxazolyl, isoxazolidinyl, 2-isoxazolinyl, morpholinyl,naphthyridinyl, octahydroisoquinolinyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxothiolanyl, phenanthridinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl, pyroazolidinyl,pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl,pyridothiazolyl, pyridothiophenyl, pyridyl, pyrimidinyl, pyrrolidinyl,pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyridinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolidinyl,thiazolinyl, thiazolyl, thienyl, thienoimidazolyl, thienooxazolyl,thienopyrrol, thienopyridin, thienothiazolyl, thienothiophenyl,thiomorpholinyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl, where alkylene isunsubstituted or monosubstituted by —(C₁-C₄)-alkyl or—(C₃-C₆)-cycloalkyl, or some or all of the hydrogen atoms in alkyleneare replaced by fluorine, R11 and R12 are each independently a hydrogenatom or —(C₁-C₆)-alkyl, R5, R6, R7, R8 and R9 are the same or differentand are each independently a hydrogen atom, —(C₁-C₆)-alkyl, OH,—O—(C₁-C₈)-alkyl, chlorine, bromine, —SF₅, —(C₀-C₄)-alkylene-N(R21)-R22,—(C₄-C₁₅)-Het, —(C₀-C₄)-alkylene-N(R21)-C(O)—R22,—CF₃—(C₀-C₆)-alkylene-O—(C₁-C₆)-alkylene-O—(C₁-C₆)-alkyl,—(C₀-C₆)-alkylene-O—(C₁-C₄)-alkylene-(C₃-C₆)-cycloalkyl or—(C₀-C₆)-alkylene-O—(C₀-C₆)-alkylene-(C₆-C₁₄)-aryl, where alkylene isunsubstituted or monosubstituted by —O—(C₁-C₆)-alkyl, with the provisothat at least one R5, R6, R7, R8 or R9 is not a hydrogen atom, R5 andR6, R6 and R7, R7 and R8 or R8 and R9, together with the ring atoms towhich they are each bonded, form a morpholine ring, where the ring isunsubstituted or monosubstituted by —(C₁-C₄)-alkyl, R21 and R22 are eachindependently a hydrogen atom or —(C₁-C₆)-alkyl.
 5. A compound asclaimed in claim 1, wherein the compound is selected from:1-{2-[3-acetylamino-5-(pentafluorosulfanyl)phenyl]-2-oxoethyl}-3-amino-6-ethoxy-[1,2,4]triazolo[4,3-b]pyridazin-1-iumtrifluoroacetate,3-amino-1-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxoethyl]-6-trifluoromethyl-[1,2,4]triazolo[4,3-a]pyridin-1-ium,3-amino-1-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxoethyl][1,2,4]triazolo[4,3-a]pyridin-1-ium,3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-trifluoromethyl-[1,2,4]triazolo[4,3-a]pyridin-1-ium,3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-5-methyl-7-trifluoromethyl-[1,2,4]triazolo[4,3-a]pyridin-1-ium,3-amino-5-chloro-1-{2-[3-methylamino-5-(pentafluorosulfanyl)phenyl]-2-oxoethyl}-[1,2,4]triazolo[4,3-a]pyridin-1-ium,3-amino-7-ethoxy-6-ethoxycarbonyl-1-{2-[3-methylamino-5-(pentafluorosulfanyl)phenyl]-2-oxoethyl}-[1,2,4]triazolo[4,3-a]pyridin-1-ium,3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-7-ethoxy-6-ethoxycarbonyl-[1,2,4]triazolo[4,3-a]pyridin-1-ium,3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-7-ethoxy-6-methylcarbamoyl-[1,2,4]triazolo[4,3-a]pyridin-1-ium,3-amino-6-chloro-1-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxoethyl]-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-ethoxy-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-isopropoxy-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-methoxy-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-6-ethoxy-1-[2-(4-methoxy-3-morpholin-4-yl-5-trifluoromethylphenyl)-2-oxoethyl]-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,1-{2-[3-acetylamino-5-(pentafluorosulfanyl)phenyl]-2-oxoethyl}-3-amino-6-ethoxy-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-cyclopentyloxy-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-cyclobutoxy-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-phenoxy-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-6-benzyloxy-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-cyclohexyloxy-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-yl-phenyl)-2-oxoethyl]-6-(2,2,2-trifluoroethoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-cyclopropylmethoxy-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-ethoxy-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-6-(1-ethylpropoxy)-1-{2-[3-methylamino-5-(pentafluorosulfanyl)phenyl]-2-oxoethyl}-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-6-(1-ethylpropoxy)-1-{2-[3-methoxy-5-(pentafluorosulfanyl)phenyl]-2-oxoethyl}-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(3-tert-butyl-5-ethoxymethylphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(3-tert-butyl-5-cyclopropylmethoxymethylphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(3-tert-butyl-4,5-diethoxyphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(3-tert-butyl-4,5-biscyclopropylmethoxyphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(3-tert-butyl-5-propoxymethylphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(3-tert-butyl-5-ethoxyphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-6-(1-ethylpropoxy)-1-[2-(3-methoxy-5-trifluoromethylphenyl)-2-oxoethyl]-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(3-tert-butyl-5-methoxyphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(3-tert-butyl-5-cyclopropylmethoxyphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(3-tert-butyl-5-cyclobutylmethoxyphenyl)-2-oxoethyl]-6-(1-ethyl-propoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(3-benzyloxymethyl-5-tert-butylphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(3-cyclohexylmethoxy-4,5-dimethoxyphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-6-butoxy-1-[2-(3-tert-butyl-5-methoxymethylphenyl)-2-oxoethyl]-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(3-chloro-5-methoxyphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(8-tert-butyl-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-diethylamino-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-piperidin-1-yl-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-ethoxy-[1,2,4]triazolo[4,3-a]pyridin-1-ium,3-amino-1-[2-(3-cyclohexylmethoxy-5-ethoxyphenyl)-2-oxo-ethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(3-bromo-5-methoxyphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-6-(1-ethylpropoxy)-1-[2-(3-isopropyl-5-methoxy-phenyl)-2-oxoethyl]-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(3-cyclohexylmethoxy-5-methoxyphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-{2-[3-(3,3-dimethylbutoxy)-5-ethoxyphenyl]-2-oxoethyl}-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(8-tert-butyl-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-2-oxoethyl]-6-ethoxy-[1,2,4]triazolo[4,3-a]pyridin-1-ium,3-amino-6-diethylamino-1-{2-[3-methoxy-5-(pentafluorosulfanyl)phenyl]-2-oxoethyl}-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-morpholin-4-yl-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(5-bromo-2,3-dimethoxyphenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(3-chloro-4,5-dimethoxy-phenyl)-2-oxoethyl]-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-{2-[3-tert-butyl-5-(2-methoxyethoxy)phenyl]-2-oxoethyl}-6-(1-ethylpropoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(3-tert-butyl-5-methoxyphenyl)-2-oxoethyl]-6-(2-methoxyethoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(3-tert-butyl-5-methoxymethylphenyl)-2-oxoethyl]-6-(2-methoxy-ethoxy)-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-yl-phenyl)-2-oxoethyl]-6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-6-(1-ethylpropoxy)-1-{2-[3-morpholin-4-yl-5-(pentafluorosulfanyl)phenyl]-2-oxoethyl}-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-6-ethyl-1-{2-[3-methoxy-5-(pentafluorosulfanyl)phenyl]-2-oxoethyl}-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-ethyl-[1,2,4]triazolo[4,3-b]pyridazin-1-ium,3-amino-6-chloro-7-diethylcarbamoyl-1-{2-[3-methoxy-5-(pentafluorosulfanyl)phenyl]-2-oxoethyl}-[1,2,4]triazolo[4,3-b]pyridazin-1-iumor3-amino-1-[2-(3-tert-butyl-4-methoxy-5-morpholin-4-ylphenyl)-2-oxoethyl]-6-chloro-7-diethylcarbamoyl-[1,2,4]triazolo[4,3-b]pyridazin-1-ium.6. A pharmaceutical composition comprising at least one compound asclaimed in claim 1 and a pharmaceutically acceptable carrier.
 7. Amethod for the prophylaxis, secondary prevention or treatment of adisorder associated with thromboses, embolisms, hypercoagulability,fibrotic changes or inflammatory disorders, the method comprisingadministering to a patient in need thereof an effective dose of acompound as claimed in claim
 1. 8. The method as claimed in claim 7,wherein the disorder is myocardial infarction, angina pectoris and othertypes of acute coronary syndrome, stroke, peripheral vascular disorders,deep vein thrombosis, pulmonary embolism, embolic or thrombotic eventscaused by cardiac arrhythmias, cardiovascular events such as restenosisfollowing revascularization and angioplasty and similar procedures suchas stent implantations and bypass operations or reduction of the risk ofthrombosis following surgical procedures such as knee and hip jointoperations or procedures leading to contact of blood with foreignsurfaces, such as for dialysis patients and patients with indwellingcatheters or disseminated intravascular coagulation, sepsis and otherintravascular events associated with inflammation, atherosclerosis,diabetes and the metabolic syndrome and the sequelae thereof, tumorgrowth and tumor metastasis, inflammatory and degenerative articulardisorders such as rheumatoid arthritis and arthrosis, impairments of thehemostatic system such as fibrin deposits, fibrotic changes in the lungsuch as chronic obstructive pulmonary disease, adult respiratorydistress syndrome or fibrin deposits in the eye following eye operationsor prevention and/or treatment of scarring.
 9. A process for preparing acompound of formula I as claimed in claim 1, comprising a) reacting acompound of formula II

where R5, R6, R7, R8, R9, Q2 and Q3 are each as defined in claim 1 and Wis chloride, bromide, mesylate or tosylate with a compound of formulaIII

in which X, R2, R3, R4 and Q1 are each as defined in claim 1, with orwithout addition of base, in a solvent to give a compound of formula I,or b) either isolating the compound of the formula I prepared by methoda) in free form or releasing it from physiologically incompatible saltsor, in the case of the presence of acidic or basic groups, converting itto physiologically compatible salts, or c) separating a compound of theformula I prepared by method a), or a suitable precursor of the compoundof formula I which, owing to its chemical structure, occurs inenantiomeric or diastereomeric forms, into the pure enantiomers ordiastereomers by salt formation with enantiomerically pure acids orbases, chromatography on chiral stationary phases or derivatization bymeans of chiral enantiomerically pure compounds such as amino acids,separation of the diastereomers thus obtained, and elimination of thechiral auxiliary groups.